Solids …….Liquids

The differences in the cleaning of equipment utilized for solid and liquid formulations are
quite significant. The distinction between these formulation types is related to how
contamination might be left on the equipment and dispersed in subsequent products.

Liquid formulations may have greater ability to penetrate equipment seals and joints, hindering their
removal. In contrast, solid formulations may have unique abilities to form aggregations of
product. This "clumping" may inhibit "wetting" by cleaning agents thereby limiting the ability to "rinse" the residual product away.
The "distribution" of the contaminant is often considered to be quite different for solid and
liquid formulations as well. Liquid products are often considered to have superior dispersion
of active ingredients uniformly across surfaces, while solid products are expected to have
more point to point variability, based primarily upon equipment configuration.

Formulation Attributes

Attributes of the formulation have been identified in the section on residues to have a great influence on the ability to clean.

In general, solid and liquid formulations represent the range
of physical product attributes and soluble and insoluble represent the ability of products within the continuum to react with the agents which are used to clean.

Non-Sterile -Sterile

 Production of sterile formulations increases the extent of cleaning operations relative to non-sterile products. Sterile manufacturing facilities must control microbial, endotoxin and particulate levels to a degree not common with non-sterile products.

Not only are the number of concerns increased but the nature of these contaminants makes the successful removal of
these items (and their validation) more difficult.

Sampling methods for these contaminant are more subjective, the analytical methods more demanding, and the validation generally
more difficult to complete.

Concerns relative to microbial and particulate control are lessened in the production of nonsterile products but are still important.

Practices which minimize the potential for contamination by "objectionable organisms" are common in the manufacture of non-sterile formulations such as oral liquids and topical products.

Highly Characterized - Poorly Characterized

 

In addition to the myriad of cleaning processes which must be evaluated, there are additional
difficulties: appropriate limits for active agents must be selected; this limit might be based
upon a not yet identified therapeutic dose.

Alternatively, using the lowest dose, or considering using the worst case might save time on scale up, provided that the appropriate
assays for these levels have been developed and validated.

Other difficulties include the requirement that appropriate analytical methods must be developed for all formulations.
Clearly, while the validation of cleaning is a difficult task in a production facility, the
unknowns inherent in clinical product manufacturing, where the product is poorly
characterized, make the task even more challenging.

Other areas where products may be poorly characterized include bioprocesses and syntheses
where vast numbers of related molecules may be formed, in addition to the primary product.
While there are generally requirements that all of these potential "contaminants" developed
during the manufacturing process be identified, these materials may not be characterized well
enough to have specific, low-level assays developed for each of them.

The establishment of appropriate limits for each of these substances is equally complicated and may not be feasible.

PDA-TECH - Highly Characterized -Poorly Characterized

 

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Highly Characterized -Poorly Characterized
The introduction of pre-approval inspection requirements for NDA and ANDA approval has resulted in greater scrutiny being placed on documentation describing the development of the formulation.

Regulatory agency expectations for cleaning validation are formidable within
the confines of marketed product manufacturing (typically highly characterized products) but
placing the same requirements upon developmental drugs (typically poorly characterized)
makes cleaning validation even more difficult.

During product development, the formulation process and equipment to be utilized in production are evaluated in order to ensure a consistent process for commercial scale manufacture.

Before the final equipment selections
are made, however, a wide variety of equipment combinations may be tried, resulting in a vast
array of cleaning combinations.

Low Risk - High Risk Drugs

Many firms have used dedicated facilities and/or equipment, or conducted cleaning verification in order to circumvent some of the inherent difficulties in processing high risk drugs.

The difficulties of reproducibly demonstrating successful cleaning may make it operationally easier to dedicate the equipment and/or facility to the production of a single product rather than attempt to clean to the necessary level of cleanliness.

The route of administration of a product may affect the level at which the product is found to be allergenic, toxic or potent.

Generally speaking, injectable products, intra-ocular
formulations, and some inhalants which provide direct access to the systemic circulation systems of patients are a much greater concern in terms of cross-contamination.

PDA TECHNICAL LITERATURE

 

Low Risk - High Risk Drugs
1.The residual limits utilized for cleaning validation are often closely related to the allergenicity/toxicity/potency of the materials in question.

2.The limits are eased when the materials being removed are generally of lower pharmacological activity.

3. At the other extreme, there are numerous materials and formulations, where even minute quantities can
have pharmacological activity.

4. The equipment and the procedures utilized to clean the
equipment might be identical, yet the production of materials with known adverse effects may require that tighter limits be achieved.

.5.Cleaning, sampling and analytical methods may need
to be refined to a high degree of sensitivity to ensure that the equipment has been properly cleaned.

PDA CLEANING VALIDATION

Product Atttibutes

1.The cleaning of equipment is closely tied to the type of materials being removed from the surface.
2.The product formulation is often the key in establishing appropriate cleaning acceptance criteria, challenge methods and sampling techniques.

INTRODUCTION TO GOOD MANUFACTURING PRACTICE

Materials of Construction

1.The materials of construction of the equipment should be considered carefully when
establishing a cleaning validation program.

2. The attributes of the surface to be cleaned will define the residue to surface interactions, identify possible contaminants and point to areas
which may not be readily cleaned or accurately sampled.

3.The CGMPs (211.65) state that,
"a) Equipment shall be constructed so that surfaces which contact components, inprocess
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 established 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 established requirements."

4.Equipment should not be reactive, additive or adsorptive with the process materials which
contact them.

5.The use of porous surfaces for multiple products should be avoided (filters,
filter bags, fluid bed drier bags, membrane filters, ultra filters).

6.Any surfaces which have these properties will require review during cleaning validation evaluations to ensure adequate
product removal and minimize the potential for cross-contamination.

7.The interaction of cleaning agents with surfaces that are likely to display these properties (e.g., seals, gaskets,
valves) should be assessed.

Non-Critical Site -- Critical Site

 

1.Critical sites are those locations in which a contaminant is in danger of affecting a single dose
with a high level of contamination.

2. Critical sites often require special cleaning emphasis.

3. It may be appropriate to establish more intensive sampling schedules for critical sites, set tighter
acceptance criteria for critical sites and ensure that enough detail is included in cleaning
procedures to provide for reproducible cleaning of critical sites.

Non-Product Contact -- Product Contact Surfaces

 

1.Traditionally, the validation of cleaning has focused on product contact surfaces.

2. Programs for the elimination of cross-contamination must address non-product contact surfaces if they
are to be truly effective.

3.In practice, cleaning validation requirements may change with nonproduct
contact surfaces in accordance with the less critical nature of these areas.

4.When establishing the requirements for non-product contact surfaces, it is important to review the
possible interactions of that area with the process.

Dedicated - Non-Dedicated Cleaning Equipment

1.The issues of dedicated and non-dedicated equipment can also arise when considering the
equipment used for cleaning.

2.CIP systems, for example, are frequently used for many different tanks in a single facility.

3.Inherently, the design of CIP systems should preclude cross-contamination through appropriate valving and back-flow prevention.

4..Care should be taken with shared devices which apply cleaning agents, such as spray balls or spray nozzles
which, themselves, may require cleaning.

5.Certainly any recirculation within the CIP system should be configured carefully during system design and monitored closely during routine
operation.

6.COP equipment, such as an ultrasonic sink, may also be used for multiple equipment loads.

7.With cleaning apparatus such as the sink, the removal of potential contaminants from the sink,
itself is a concern.

8. Sinks and washers frequently use recirculation systems to economically
remove residuals from surfaces without undue waste.

8.The cleanliness of the re-circulated materials should be evaluated during cleaning validation to ensure that contaminants are not
being re deposited on the equipment to be cleaned.

Dedicated - Non-Dedicated Manufacturing Equipment

1.Dedicated equipment is used solely for the production of a single product or product line.
Concerns over cross-contamination with other products are markedly reduced.

2.Dedicated equipment must be clearly identified with the restrictions of use in order to prevent potential
errors during cleaning and preparation.

3.Where the same piece of equipment is utilized for a range of product formulations, (i.e., non dedicated
equipment), the prevention of cross-contamination between products becomes the
main objective in the cleaning validation effort.

4.Clearly, cleaning non-dedicated equipment represents a more significant obstacle to overcome.

Equipment Characteristics / Materials of Construction

1. Equipment usage during production is another important aspect to consider in establishing a cleaning
validation program.

2.It is important to understand not only the range of products that are likely to
come into contact with the various equipment surfaces, but also the role that the equipment plays in
the production train.

3.This will help to establish the contamination and cross-contamination potentials
of the equipment.
4.Equipment design characteristics, as established during product development, are often driven by
equipment functionality and the requirements of the process.

5.With the current emphasis on cleaning validation, it makes sense that "cleanability" be a key criterion in the design of equipment.

Pharma GMP Hub: PDA CLEANING VALIDATION

Pharma GMP Hub: PDA CLEANING VALIDATION

CIP vs COP

Clean-In-Place (CIP)	Clean-Out-of-Place (COP)
The cleaning of large pieces of equipment may be performed in the equipment's permanent location, generally in a configuration very similar to that in which it is utilized for production.	Smaller equipment items are frequently transported to a designated cleaning or wash area where the cleaning procedure is performed.
Easy to handle	Transferring of item may lead to cross contamination
Automated or manual method adopted	Automated or manual method adopted

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Cleaning Program Criteria

Automated Cleaning	Manual Cleaning
Automated cleaning will usually provide reproducible results.	Manual cleaning is a universal practice within the pharmaceutical industry
Process control is inherent in automated systems and process monitoring is frequently integral with the control system	There are many pieces of equipment and portions thereof for which construction and/or configuration make manual cleaning a necessity.
The validation of an automated system requires that the cycle is proven to be rugged and will provide reproducible results under a given range of operating conditions.	The control of manual cleaning is accomplished by operator training, well defined cleaning procedures, visual examination of equipment after use and prior to the next use, and well-defined change control programs.
Control system validation is a large part of the validation of an automated cleaning system.	It may be desirable to identify worst case cleaning situations (in terms of operator experience and/or cleaning methodology) for validation purposes.
	With manual cleaning, concern must also be given to the ruggedness of the method. Successful reproducibility is a function of strict adherence to written procedure

 

 

 

Continues

Cleaning Program Criteria

1.When establishing a cleaning validation program, it is important to first characterize the types of
cleaning that are used in the facility.

2.The cleaning methods that are used in a facility can reveal
important factors with regard to process control, process reproducibility, the best ways in which to
challenge the process, the best ways in which to collect samples and the best ways in which to
monitor cleaning effectiveness during routine cleaning.

Continues

Use of the Cleaning Continuum

Table 1: The Cleaning Continuum
Manual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Automated Cleaning
Clean-out-of-Place (COP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clean-in-Place (CIP)
Dedicated Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-Dedicated Equipment
Product Contact Surfaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-Product Contact Surfaces
Non-Critical Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Critical Site
Minor Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Major Equipment
Low Risk Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . High Risk Drugs
Highly Characterized . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Poorly Characterized
Sterile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-Sterile
Solid Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Liquid Formulations
Soluble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Insoluble
Single Product Facility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Multiple Product Facility
Campaigned Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-Campaigned Production
Simple Equipment Train . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Complex Equipment Train

Continues

Use of the Cleaning Continuum

Use of the Cleaning Continuum

 

1.The cleaning continuum provides some of the primary points to consider in any cleaning validation
program.

2. The continuum helps firms to establish the parameters which are critical factors for
individual products, thereby enabling them to set priorities, develop grouping philosophies and
establish the "scientific rationale" which will govern the cleaning program.

3.The continuum will assist in determining which processes, equipment and products represent the greatest concerns and may
help to establish the criticality of cleaning limits and methods.

4.The continuum should be used during
the initial phases of defining a cleaning validation program or during new product development.

 

 

Continues

pda technical literature cleaning validation

PDA CLEANING VALIDATION CLEANING CONTINUUM

PDA TECHNICAL LITERATURE CLEANING VALIDATION REPORT 29 CLEANING VALIDATION

Scope

This paper applies to biopharmaceutical, bulk pharmaceutical and finished dosage form operations;
liquid, dry, solid and semi-solid dosage forms are covered in both sterile and non-sterile presentations.
Both clinical and marketed product cleaning validation programs are identified

PDA TECHNICAL LITERATURE 29 POINTS TO CONSIDER

1.2 Purpose
The purpose of this publication is to identify and discuss the many factors involved in the design,
validation, implementation and control of cleaning programs for the pharmaceutical industry.
The document does not attempt to interpret CGMPs but provides guidance for establishing a cleaning
validation program. It identifies the many factors to be considered for all segments of the
pharmaceutical industry. It also identifies specific points to be considered by dosage form
manufacturers, manufacturers of clinical trial materials (CTMs) and manufacturers of bulk
pharmaceutical chemicals and biochemicals. The report covers the different approaches which may
be appropriate for the different stages of product development from the early research stages to the
commercially marketed product.

STERILE FILTRATION

                                                                                                                                                               
                                                                                                                                                     
                                                                                                                                                                               
                                                                                                                       
 

PDA CLEANING VALIDATION

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