VISIBLE RESIDUE LIMIT- SCOPE OF IMPROVEMENT

ABOUT AUTHOR:
Arsh Chanana
Department of Pharmaceutics,
Seth G.L. Bihani S.D. College of Technical Education Sri Ganganagar.
arshchanana@ymail.com

ABSTRACT-
Pharmaceutical manufacturers must validate their cleaning process to ensure compliance with cGMP regulations. Minimizing equipment downtime significant impact on efficiency and economics of pharmaceutical production. The main purpose of cleaning validation is to provide effective and consistent cleaning in a given pharmaceutical production which can prevent cross contamination and adulteration of drug products with other active ingredients unintended compounds or microbiological contamination, leading prevention of several serious problems. So it is necessary to validate the cleaning procedures to ensure safety, efficacy and quality of the subsequent batches of drug product or API’s. Cleaning validation is also essential to meet regulatory requirements. The benefits of “cleaning validation” are compliance of regulatory requirements and potential problems, previously unsuspected. Which could compromise the safety and efficacy of drug products.

REFERENCE ID: PHARMATUTOR-ART-1795

1) INTRODUCTION
GMP Issues
Cleaning of process equipment has been part of the good manufacturing practices (GMPs) for pharmaceutical manufacturing for many years. It included recommendations for written procedures, cleaning logs, and appropriate design of equipment to facilitate cleaning. Good cleaning practices are necessary to preserve the safety and efficacy of the manufactured drugs and drug products. Possible consequences of inadequate cleaning include cross contamination (the presence of active drug in another drug product at an unacceptable level), the presence of foreign material (e.g., a cleaning agent, solvent, or excipient from another drug product), the presence of microbial contamination (numbers and/ or species of microbes), or the presence of endotoxins (particularly in parenteral or ophthalmic products).

The presence of such contaminants in a drug product may pose safety problems depending on the level of the contaminant. Such contaminants may also affect the efficacy of a drug product; effects could include modifying the bioavailability of the APIs, the dissolution time of tablets, or the stability of the finished drug products. Needless to say, failing to follow GMPs relating to cleaning processes also renders the product ‘‘adulterated’’ and subject to regulatory action. [17]

Expectation of Validation
Validation in the pharmaceutical and medical device industry is defined as the documented act of demonstrating that a procedure, process, and activity will consistently lead to the expected results. It often includes the qualification of systems and equipment. It is a requirement for Good Manufacturing Practices and other regulatory requirements. [18]

“There shell be written procedure for production and process control designed to assure that the drug product have their identity, strength, quality and purity they purport or are representedto posses.”[8]

Since a wide variety of procedures, processes, and activities need to be validated, the field of validation is divided into a number of subsections including the following:

Cleaning Validation

Process Validation
Analytical Method Validation
Computer System Validation

Since about 1990 the regulatory expectations are that the certain cleaning processes in pharmaceutical manufacturing be validated. As cleaning is a process, the principles of process validation apply to the cleaning process. In 1996, the FDA proposed amendments to the GMPs which clearly defined validation of cleaning processes as a GMP requirement. The U.S. FDA took the lead in requirement of validation of cleaning processes, and other agencies also issued similar requirements. Although the initial emphasis was on cleaning validation related to finished drug products, additional guideline documents clarified that cleaning validation should be considered for active pharmaceutical ingredients and for pharmaceutical excipients also. [17]

Applicability of Cleaning Validation
It should be noted that these cleaning validation requirements apply only to critical cleaning processes. Although GMPs require the cleaning of (and cleaning SOPs for) floors, walls, and the outside of process vessels, such processes are not considered critical cleaning processes. The processes that are critical generally include processes for cleaning product-contact surfaces of equipment or utensils. It is these product-contact surfaces that have the possibility of directly contaminating the next product made in the same equipment. In addition, the cleaning of non-product-contact surfaces that could reasonably indirectly contaminate subsequently manufactured products should also be considered for cleaning validation. For example, some companies have, either on their own or because of regulatory requirements, validated the cleaning of internal surfaces of lyophilizers used for production. On the other hand, validation of cleaning between lots of the same product is not necessarily a requirement .This is based on the fact that cross-contamination of the active is not an issue. However, other concerns such as contamination with degradation products, with cleaning agent residues, or with microorganisms may suggest that such cleaning is critical, and therefore should be validated. [17]

The concepts of "clean-hold time" and "dirty-hold time" have been part of cleaning validation since its inception. Clean hold time is generally considered to be the time between the completion of cleaning and the initiation of the subsequent manufacturing operation. Dirty hold time can begin when the clean equipment is initially soiled, but more often is defined as the time between the end of manufacturing and the beginning of the cleaning process. Intuitively, it makes sense to be concerned about both hold times. Dirty equipment is harder to clean the longer the hold time, and clean equipment has a greater chance of becoming soiled as hold time increases.

FDA requirements
Regulatory authorities have been issuing guidelines regarding cleaning frequently. A validated cleaning procedure is a must for attaining cGMP norms in a pharmaceutical manufacturing potent steroids products as well as non-steroidal products using common equipment. FDA considers the potential for cross-contamination to be significant and to pose a serious health risk to the public. [8]

Current GMP requirements for cleaning validation

FDA expects firms to have written standard operating procedures (SOP) detailing the cleaning process used for various pieces of equipment.
If firms have a specific cleaning process for cleaning between different batches of the same product and use a different process for cleaning between product changes, FDA expects the written procedures to address these different scenarios.
If firms have one process for removing water-soluble residues and another process for non-water soluble residues, the written procedure should address both scenarios and make it clear when a given procedure is to be followed.
It is required by the FDA, in the general validation procedure, that the personnel responsible for performing and approving the study should comply with the acceptance criteria and the revalidation data.
FDA expects firms to prepare specific written validation protocols in advance for the studies to be performed on each manufacturing system or piece of equipment which should address such issues as sampling procedures, and analytical methods to be used including the sensitivity of those methods.
It is expected that firms conduct the validation studies in accordance with the protocols and document the result of studies.

Final validation report is to be approved by the regulatory board which states whether or not the cleaning process is valid. [9]

Objectives-
The objectives of equipment cleaning and cleaning validation in an Active Pharmaceutical Ingredient (API) production area are same as those in pharmaceutical production area. In both these areas efforts are necessary to prevent contamination of a future batch with the previous batch material. The cleaning of 'difficult to reach' surface is one of the most important consideration in equipment cleaning validation. Equipment cleaning validation in an API facility is extremely important as cross contamination in one of the pharmaceutical dosage forms, will multiply the problem. Therefore, it is important to do a step-by-step evaluation of API process to determine the most practical and efficient way to monitor the effectiveness of the cleaning process. It is necessary to validate cleaning procedures for the following reasons

It is a prime customer requirement since it ensures the purity and safety of the product.
It is a regulatory requirement in Active Pharmaceutical Ingredient product manufacture.
It also assures the quality of the process through an internal control and compliance. [9]
To minimize cross contamination, contamination leads to inferior quality of final products produced and hence cause considerable loss to the company.
To determine the efficiency of cleaning process and to provide documented assurance that results in equipment that is clean enough to prevent contamination in future dosage forms.
To do trouble shooting in case of problems identified in the cleaning process and to give suggestion to improve the process to prevent future contamination. [8]

2) CLEANING PROCESSES
The overall cleaning process comprises the soiled equipment, a cleaning method with the associated cleaning equipment, a cleaning agent(s), and process parameters (time, temperature, etc.). These factors should all be captured in a cleaning standard operating procedure (SOP).

2.1 Equipment Design
As regards to the equipment to be cleaned, this depends on both the equipment itself and the residues to be removed. Ideally the equipment to be cleaned has been designed with cleaning in mind. Design characteristics may be different for manual versus automated cleaning.The equipment design may also affect the extent of disassembly of the equipment as part of the cleaning process. [17]

2.2 Types of contaminations-
* Cross contamination with active ingredients-
Contamination of one batch of product with significant levels of residual active ingredients from a previous batch cannot be tolerated. [9] If the cleaning procedure is not effective, residual contamination of an active chemical processed earlier may be passed on to the next batch processed in the same equipment. Now-a-days, there are several potent drugs which clinically may have significant interaction between pharmacological active substance. [14]

One of the real dangers in cross-contamination of active ingredients is that by being contaminated the product becomes truly a multiple ingredient product instead of a single active ingredient. Depending on medical effects, the contaminant may enhance the action of the intended active (referred to as having a synergistic effect). [10]

* Contamination with unintended materials or compounds-
While inert ingredients used in drug products are generally recognised as safe or have been shown to be safe for human consumption, the routine use, maintenance and cleaning of equipments provide the potential contamination with such items as equipment parts, lubricants, chemical cleaning agents and pieces of cleaning tools such as brushes and rags. [9] [14]

Some pharmaceutical operations may find it necessary to use fairly toxic materials for cleaning purposes for stubborn residues. This is particularly true in the manufacture of active pharmaceutical ingredients (APIs). [10]

* Microbiological contamination-
Maintenance, cleaning and storage conditions may provide adventitious micro organisms with the opportunity to proliferate within the processing equipment. [9] Various pharmacopoeias prescribe microbial examination of some finished products. The Indian GMP text state that the finished products should be free from pathogens. The British Pharmacopoeia (B.P.) recommends limits of total aerobic count (TAC) in different dosage form. [14] A major contributing factor is the storage of equipment in a wet condition. This provides a natural medium in which bacteria can grow. Although we have tended to identify and control microbial contamination for sterile manufacturing situations by monitoring bioburden and endotoxin levels and by environmental monitoring programs, we may not yet have given adequate attention to potential microbial contamination in non-sterile areas. [10]

* Contamination by Other Miscellaneous Materials
In addition to the usual expected or anticipated list of potential contaminants in a pharmaceutical operation, many other less likely materials can and do contaminate products. A partial list includes equipment parts, filling equipment, paper filters, micron filters, gowning material, fibers and rubber particles from gloves, cleaning aids such as brush bristles, cloth, and cotton fibers from rags and wiping materials, lubricants, fragments from gaskets and seals, fibers from swab testing kits, and dust and particulates. [10]

2.3 Cleaning Methods
Although cleaning methods are sometimes divided into clean-in-place (CIP) and clean-out-of-place (COP) applications, it may be more useful to consider two significant features of cleaning methods to provide broad categorizations of cleaning processes. Extent of automation one factor involves the extent of automation. At one extreme of the ‘‘automation’’ continuum is the fully automatic process—no operator intervention is required for preparation of the cleaning solution, for the cleaning cycle, or for any disassembly or reassembly. [17]

2.4 Extent of disassembly
A second continuum for cleaning processes involves the degree of disassembly (and consequent reassembly).At one extreme is equipment that requires no disassembly at all (true ‘‘clean-in-place’’). At the other extreme is equipment that requires disassembly of each component part for cleaning. Disassembly (and reassembly) is preferably avoided for several reasons, including the time it adds to the overall cleaning process (equipment downtime), the concern over damage to the equipment because of stresses during the disassembly/ reassembly process, and the concern over incorrect reassembly. [17]

2.5 Simplification of cleaning processes
Design of a cleaning process must be taken into consideration not only the nature of the process itself but also the engineering design of the equipment to be cleaned, the various products manufactured in the equipment (such products become ‘‘soils’’ to be cleaned at the end of manufacturing), and the cleaning process parameters In many pharmaceutical facilities, the objective is to make the process as simple and universal as possible so that one cleaning SOP can be used either for all manufactured products made in the same equipment or for all equipment cleaned in the same process. This simplifies documentation and training and may (because of grouping or bracketing strategies) simplify validation. [17]

2.6 Cleaning process steps
The general steps or stages of most cleaning processes involve the following:

Disassembly and Isolation
Prewashing (or Pre rinsing)
Washing
Rinsing
Drying
Reassembly and Storage

3. Automated CIP systems
The discussion of CIP processes deserves special comment because of industry trends to use CIP systems. As used in a broad sense, CIP refers to any system in which the equipment is cleaned with no or minimal disassembly. In a more narrow sense (and in this sense it is more commonly used now), CIP is used to refer to systems in which one or more spray devices is placed in the equipment to be cleaned. A control unit, comprising a pump, associated valves, and a PLC (programmable logic controller), pumps a cleaning solution from a storage tank through the spray device(s). The spray device(s) is engineered and placed so that solution is either directly sprayed or else sprayed so that the solution cascades down the equipment sidewalls to cover all surfaces of the equipment for effective cleaning. In a non-recirculating CIP system, the cleaning solution passes once through the process vessel and associated piping, and then goes to drain. In a recirculating system, the cleaning solution passes through the process vessel and associated piping and then back to the cleaning solution storage tank. It is then pumped through the spray device again, for multiple passes. [17]

4) Cleaning Agents
Aqueous vs. non-aqueous
In addition to the cleaning method used, the cleaning agents used in the washing step are critical. It should be appreciated that selection of the cleaning method and cleaning agent(s) are somewhat interdependent. Selection of a cleaning method may limit the available cleaning agents that can effectively be used in that process. For example, a CIP process requires a low foaming aqueous cleaning agent, while extent of foam may not be critical for manual cleaning. Cleaning agents may be divided into aqueous and non-aqueous cleaning products. Non-aqueous products are typically solvents, and are more common in cleaning in the bulk manufacture of an active pharmaceutical ingredient (API). Typically, the solvent used for cleaning is the same as that used for manufacture. The cleaning effectiveness depends on the solubility of the residue(s) in the solvent at the temperature of cleaning. Particularly for cleaning of distillation columns, refluxing with a volatile solvent is a common practice for effective cleaning. The trend in the manufacture of APIs is to move away from solvent cleaning to aqueous cleaning. However, it should recognized that in many cases this not practical, and even if it is, the aqueous cleaning may be followed by one or more solvent flushes to remove the water from the process vessels. [Swarbrick, 2007]

4.1 Types of aqueous cleaning agents
Aqueous processes involve cleaning with water and, optionally, other ingredients to assist in the cleaning process. If aqueous cleaning can be suitably performed, it is preferred over solvent cleaning because of cost issues (including the cost of the solvent as well as the costs of disposal or reclamation of the solvent) and because of environmental issues relating to the use or emissions of solvents. In aqueous processes, the use of water alone should be considered because it eliminates the concerns over having to consider potential contaminants from the cleaning agent during cleaning validation. However, in most cases, the performance characteristics of various aqueous cleaning agents more than overcome the concerns about cleaning agent residues (particularly if the cleaning agents selected are free-rinsing). The successful use of water alone for the washing step depends solely on the solubility of the residues in water at the temperature of cleaning, and may not typically provide other cleaning mechanisms such as emulsification and dispersion. Therefore, use of water alone may not meet other cleaning objectives such as short processing times. Another option for aqueous cleaning involves the use of commodity chemicals, including alkalis such as sodium or potassium hydroxide, acids such as phosphoric or citric acid, or sodium hypochlorite solution. These are typically diluted in water at levels of 0.05– 1% (w/w), and the resultant solution is typically used at elevated temperatures (45–80_C). Commodity chemicals may provide better cleaning than water alone, and they do so at a relatively inexpensive cost. Residue detection of cleaning agents during validation is relatively straightforward because there is usually only one chemical species to detect from the cleaning agent itself. A third option for aqueous cleaning is to use a formulated cleaning agent. These formulated products usually contain several functional agents including a surfactant(s), an alkalinity or acidity source, water miscible solvents such as glycol ethers, dispersants such as low-molecular-weight polymers, and various builders such as chelants. The main advantage of such formulated cleaning products is that they are multifunctional because of the variety of components; each component broadens the performance in terms of being applicable on a wider variety of soil types. Well-formulated products thus enable a pharmaceutical manufacturer to use one cleaning agent in one cleaning SOP to effectively clean not only the variety of components in a finished drug product, but also a broader range of finished drugs themselves. It should be noted in the former case that for many (if not most) finished drugs, it is the excipients in the finished drug that are more difficult to clean (as compared to the cleaning of the active ingredient). However, the selection of a formulated cleaning product necessitates that the pharmaceutical manufacturer knows the ingredients in the product, both as a check on the consistency of the formulation over time and to effectively establish residue limits for the cleaning agent. [17]

4.2 Basis of selection of cleaning agent
The selection of an aqueous cleaning system is simplified if only water alone, or water and a commodity chemical alone, are used. The cleaning performance can be somewhat predicted based on solubility characteristics (at the appropriate pH) or by consideration of the peptizing performance of alkalinity on protein or the oxidizing action of sodium hypochlorite on denatured protein. In the case of formulated multifunctional cleaning agents, the performance is more difficult to predict based on chemistry alone, and an acceptable cleaning agent is preferably selected based on experience or on laboratory studies. The selection of cleaning agents is also complicated by the fact that sometimes proper cleaning necessitates the use of two cleaning agents at the same time (a primary cleaning agent and a functional additive of some sort), or by the use of two cleaning agents in succession (for example, the use of an alkaline cleaning product followed by an acidic cleaning product).

4.3 Cleaning Parameters
While selection of the cleaning method and cleaning agent(s) is important, equally important are the various parameters to consider in the overall cleaning system. These include cleaning process parameters as well as parameters related to the system actually cleaned. Probably the most important cleaning process parameters are the time of cleaning, the temperature of cleaning, the concentration of the cleaning agent, the water quality, the impingement action of the cleaning solution, and any mixing in the cleaning solution.

Time
Temperature
Cleaning agent concentration
Water quality
Impingement
Mixing
Nature of the surface
Condition of soil
Amount of soil

5) CLEANING STRATEGIES IN LIGHT OF VALIDATION
Although cleaning processes should be primarily based on what is necessary for good cleaning, they may be modified somewhat based on the regulatory needs for validation. As most pharmaceutical companies will want to validate a cleaning process and not have to do additional significant revalidation work in the near future, this may limit the selection of cleaning agents. As a key part of any validated process is consistency and control, cleaning SOPs for validated processes will also generally have more detail and specificity.

Cleaning for Multiproduct Equipment
Several strategies are possible for cleaning of equipment used to make two or more different products. One option is to optimize a cleaning process for each product made on the equipment. This may mean different cleaning agents for cleaning after each manufactured product, although usually what it means is that the same cleaning agent is used under different process conditions (such as time and/or cleaning agent concentration).

Cleaning in Campaigns
Cleaning between lots of the same product made successively on the same equipment in a campaign may allow for less aggressive cleaning procedures. The reason is that in such cleaning there is no concern about cross-contamination with an active from a different product. [17]

6) VALIDATION ISSUES IQ/OQ/PQ
According to GMP definition Validation is "Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes." All validation activities will incorporate a level of Impact Assessment to ensure that systems, services and products directly influenced by the testing have been identified^. Cleaning validation is a type of process validation, and the principles of process validation apply equally to a cleaning process. This includes installation qualification (IQ), operational qualification (OQ), and process or performance qualification (PQ). [17] The use of visual inspection as a criterion for equipment cleanliness has always been a component of cleaning validation programs. Mendenhall proposed the use of only visual examination to determine equipment cleanliness as long ago as 1989. He concluded that visible cleanliness criteria were more rigid than quantitative calculations and clearly adequate. The US Food and Drug Administration limited the use of visually clean criterion between lots of the same product. LeBlanc raised the question of whether a visible limit as the sole acceptance criterion could be justified. [2]

7) Residue Limits

DETERMINATION OF ACCEPTABLE LIMITS FOR THE CLEANING PROCESS-
Determining what is an acceptable amount of residue remaining on the equipment is at the very heart of cleaning verification and validation. The determination of acceptable carryover limits for pharmaceutical equipment and facilities is actually addressing the question of “What is clean?” To those who feel that equipment and facilities should always be cleaned to the level of analytical detectability. I will only say that approach is certainly always acceptable, and in some cases, a very reasonable approach. In most cases, however, cleaning to the lowest level of analytical detectability has a couple of major disadvantages. The first problem with this approach is that current analytical capability is so incredibly sensitive that the previously manufactured product(s) can almost always still be detected even after extensive cleaning. As a consequence, most cleaning procedures would need to be much more robust and detailed than those in current use. It is already quite common in the pharmaceutical industry for the cleaning process to require much more time than the actual production time to manufacture product, thus the inadequacy of current cleaning procedures is the first disadvantage. The second major disadvantage of this approach is that analytical technology, and thus the sensitivity of methods, is constantly changing and improving. Translating this factor into impact on the cleaning program would mean that if the limit was set as the level of analytical detectability, cleaning validation would need to be repeated every time a new, more sensitive analytical method becomes available. This is not practical or even feasible for most pharmaceutical operations. To those who still aspire to zero level of cross-contamination, I would only add that we have different categories of clean rooms (e.g., class 100, class 1000, class 100,000). We do not have a class that signifies no contamination; even our most stringent classification of pharmaceuticals, sterile products, is not absolutely pure. The regulatory requirement is that the probability of a non-sterile unit (PNSU) must not exceed 1 in 10⁶ (i.e., 1 in a million). This is due to the fact that it is not possible to have 100% confidence that not a single unit will be non-sterile. It is simply not feasible, considering the nature of the physical facilities, manufacturing conditions, and imperfections in the testing process. While there is nothing wrong with our desire to produce the finest, highest quality products humanly possible, it will not be possible to achieve zero carryover and still have the products be affordable to the patient. The actual calculation or determination of limits will depend upon each individual manufacturing situation and thus must be customized for a given company or cleaning situation. Even companies with multiple manufacturing facilities may need to consider different approaches to setting limits for each individual manufacturing site, thus the setting of limits must be customized. There are many factors that should be considered in setting limits. The following list indicates some of the factors, but is not necessarily all-inclusive. In reviewing this list, please note that some of the factors relate to other products manufactured in the same equipment or the same facility. In other words, you must consider not only the potentially contaminating product, but also the other products that may be subsequently manufactured in the same equipment or facility. [10]

FACTORS TO CONSIDER IN SETTING LIMITS

The nature of the primary contaminating product

The medical dosage of the primary contaminating product

The toxicity of the primary contaminating product

The solubility of the primary contaminating product in the cleaning media

The inherent difficulty of cleaning the equipment

The nature of the cleaning process (i.e., automated versus manual)

How the product will be used by the patient or the customer

The nature of other products made in the same equipment

The medical dosage of the contaminated product

The batch size of other products made in the same equipment

There are many bases for established limits for cleaning processes-

Based on medical dose combined with a safety factor
Based on toxicity
Based on analytical detectability
Based on the process capability of cleaning process
Based on level of visual detectability

* Based on medical dose combined with a safety factor
Medical dosage level is probably the most common basis for limit calculations in the pharmaceutical industry. It is based on allowing a certain fraction of a daily dose to carry over to a daily of following products. The fraction that reduce the dosage is referred to as a safety factor or a risk assessment factor and takes the form of a fraction such as 1/100^th, 1/1000^th, of 10000^th of the original daily dose.

* Based on toxicity
This method of calculation is based on the use of animal toxicity data to determine limits. As mentioned earlier, this method is particularly suited for determining limits for materials that are not used medically. This method is based upon the concepts of acceptable daily intake (ADI) and no observed effect level (NOEL) developed by scientists in the Environmental Protection Agency the U.S. Army Medical Bioengineering Research and Development Laboratory and the toxicology department at Abbott Laboratories. This method has also been recently used to calculate the limits of organic solvent residues allowed in APIs. [8]

* Based on analytical detectability-
In certain instance, it may be necessary to base the cleaning limit on the level fo analytical detectability. This has become relatively common for biotechnology products derived from bacterial fermentation or monoclonal antibody biosynthesis. Often these situation involves dedicated manufacturing facility and several types of analysis may be carried out on each sample. The approaches are conservative in nature due to the serious nature of any potential cross-contamination events.

* Based on the process capability on cleaning process-
Another approaches for establishing limits is the use of process capability studies. This approach has been used for products that have a long history and for which the analytical method may be somewhat non-specific nature.

* Based on level of visual detectability-
The standard of visual cleanliness is commonly applied to the evaluation of surface contamination. Numerous published studies have examined the visually clean standard as a means of verifying cleaning effectiveness in pharmaceutical manufacturing, and methods for the quantitation of visible residue limits (VRLs) have been provided. Current methods for establishing VRLs are not statistically justifiable, however. The author proposes a method for estimating VRLs based on logistic regression. [11]

Visually clean (VC), a term that refers to inspection with the naked eye, is a common cleanliness standard employed for evaluating surface contamination and cleaning in high-technology manufacturing, including that of pharmaceuticals, where surface cleaning is of utmost importance. The importance of the VC standard for pharmaceutical manufacturing is evident in the following facts

It is one of the acceptance criteria for establishing the limits for cleaning-validation (CV) studies.
Visual examination of equipment surfaces for cleanliness immediately before use is required by good manufacturing practice (GMP) regulations.
Even before the issuance of the GMP regulations, most companies used to a VC standard.
A VC approach to controlling cross-contamination in processing and manufacturing operations provides a practical and effective method of risk management.
It is one of the means of evaluating cleaned surfaces during the development, optimization, and validation of cleaning processes.
It is the only tool available to operators for examining equipment surfaces to verify that they have been cleaned effectively
Manufacturers employ it for routine monitoring of the cleaning process. [11]

Limit in next product
It is important in any discussion of ‘‘residue limits’’ to understand that limits for a cleaning process may be expressed in different ways. This includes the limit of the residue in the subsequently manufactured product, the limit of the residue on the cleaned equipment surfaces, and the limit of the residue in the analyzed sample. These are all related, but they are usually different numbers. For an active ingredient in the cleaning of a finished drug product, the limit in the next product is usually calculated based on application of a safety factor (usually 0.001 or lower) to the minimum daily dose of that active in the maximum daily dose of the subsequently manufactured product. The activity or level of APIs in the subsequently manufactured product is irrelevant unless there is information about unusual deleterious interactions. This calculation is also independent of manufacturing issues such as batch size and equipment surfaces areas, and can be calculated solely on information about the dosing of the two products as follows:

L1 = MinDA*SF
-------------------
MaxDSP

where L1 is the limit of the APIsin the next product, MinDA is the minimum (daily) dose of the APIs(the target residue), MaxDSP is the maximum daily dose of the subsequently manufactured drug product, and SF represents an appropriate safety factor. Care needs to be paid to selection of units; the L1 limit is usually expressed in mg/g (or ppm).

Limit per surface area
The next limit calculated is usually the limit per equipment surface area. This is calculated based on the limit in the next product, the batch size of the subsequently manufactured product, and the equipment shared surface area. This is expressed as:

L2 = L1 * BS
----------------
SSA

where L2 is the limit per surface area, BS is the batch size, and SSA is the shared surface area. Units should be consistent, and the L2 limit is usually expressed in units of mg/cm^2.

Limit in analytical sample
The next limit is the limit in the analytical sample. If the sampling method involves swabbing, the surface area swabbed and the amount of diluent used for desorbing the swab must be considered. The limit per swab sample is then calculated as:

L3 = L2 * SA
-----------
AD

where L3 is the limit per analytical sample, SA is the swabbed area, and AD is the amount of diluent for swab elution. Here again units need to be consistent, and the L3 limit is usually expressed as mg/g or mg/ mL. It should be clear that the limit in the analytical sample can be manipulated by changing the area sampled (higher areas result in larger limits per analytical sample) or the amount of diluent used (lower amounts result in larger analytical sample limits). If a sampling rinse is used (in place of swabbing), SA effectively becomes the total surface area of the equipment, and AD becomes the volume of solution used for the sampling rinse. [Swarbrick, 2007]

Non-dose limits
For residues (such as cleaning agents) that do not have a defined dose, some measure of toxicity, such as an acceptable daily intake (ADI), is used for residue limit purposes. If the subsequently manufactured product is an in vitro diagnostic (IVD), and has no defined dose, then some evaluation of the effects of target residues on the performance or stability of the IVD product should be performed. These non-dose factors are used only for the L1 limit; there are no changes for calculation of L2 and L3 limits.

Limits for multiple subsequent products
When a residue limit is to be calculated for a product where there may be more than one subsequently manufactured product, calculations should be made to compare the surface area residue limits (L2 limits) by using each subsequent product. If the manufacturing order is not to be restricted, the cleaning validation of the first product should be established using the lowest surface area limit. [5,17]

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7.1 Sampling Procedures
Sampling procedures for cleaned surfaces can be divided into four types.

Direct surface sampling
Swab sampling
Rinse sampling
Coupon Sampling
Solvent Sampling

7.2 Analytical Methods
Relationship to target residue The analytical method selected to measure the target residue must provide a direct measurement of that target residue. When regulatory authorities first began requesting that cleaning be validated, some companies merely tested the rinse water by USP Purified Water specifications to determine if the equipment was clean. The rationale was that the effluent met the same standard as the incoming water. Regulatory authorities, quite rightly rejected such arguments (because of the possibility of unacceptable levels of potent drugs being present, and because of the possibility that the target residue not being removed in the rinsing procedure), and requested that analytical techniques target the specific residues of concern. However the requirements for analytical methods for residue determination are slightly different from methods for actives level determination in finished product in one important way. For finished product actives determination, a method is required to unequivocally measure the active in the presence of known potential interferences and provide an exact level of the active present. For cleaning validation residue analysis, it is not so as important to know exactly how much residue is present as to know that the amount present is below the acceptance criteria in the validation protocol. Analytical techniques to be used for cleaning verification can include the following: Visual inspection under ‘white’ and UV light; Total Organic Carbon – useful for evaluation of water-soluble compounds (recognising that this method is not specific for the compounds of interest); UV spectroscopy; and, most frequently, chromatographic methods. For this reason both specific and non-specific analytical methods can be used for residue detection purposes. [17]

7.3 Specific and non-specific methods
A specific method detects unique compounds in the presence of potential contaminants. Ex: HPLC. Non-specific methods are those methods that detect any compounds that produces a certain response

Ex: Total Organic Carbon (TOC), pH and conductivity. [9]

High performance liquid chromatography
Capillary electrophoresis
Total organic carbon (TOC)
Ion chromatography
Thin layer chromatography (TLC)
Atomic absorption spectroscopy (AAS)
Bioluminescence
Optically simulated electron emission (OSEE)
Portable mass spectrometer
Specificity of methods

Sampling/Analytical Method Recovery
The sampling method chosen must be challenged in combination with the analytical procedure to determine the recovery of the sampling method. This is typically a laboratory study involving spiking a model surface with the target residue and performing the sampling procedure on the surface and measuring the residue with the analytical procedure. The amount of residue measured is compared to the amount spiked to give a percent recovery. Recoveries of greater than 80% are considered good, but recoveries of greater than 50% are acceptable. As the analytical values have to be transformed by the recovery values, it is desirable to obtain as high a recovery as consistently possible. [17]

8) CONTROL ISSUES
Issues in Cleaning
GMPs require that procedures be in place to limit objectionable microorganisms in both non-sterile and sterile drug products. This should be interpreted to include both the number of organisms as well as the type (species) of organism. Protection of subsequently manufactured product from microbial contamination can be accomplished in part by effective cleaning, by a separate sanitizing step, and/or by storage procedures. In many cases effective microbial control is achieved by a good aqueous cleaning process. The conditions of cleaning can either physically remove microbes, or these conditions (hot alkaline or acidic aqueous conditions) can be conducive to the destruction of microbes. The use of hypochlorite for removal of denatured proteins also serves as an effective oxidizing biocide. If cleaning alone does not achieve adequate microbial reduction, the use of either a chemical sanitizer or elevated temperature (steam or hot air) can be considered. Chemical sanitizers include hydrogen peroxide, peracetic acid, quaternary ammonium chlorides, and alcohols; as a general rule phenolic sanitizers are not used for process equipment because of the difficulty of rinsing from equipment surfaces. If the sanitizer leaves a residue, then a final rinse should be considered to reduce that residue to an acceptable level.

Issues in Storage
One major regulatory issue in the cleaning of equipment is the possible microbial proliferation due to improper storage, such as in a wet condition or with pools of water. The preferred method for dealing with such concerns is to effectively dry the equipment before prolonged storage. An alternative (but less desirable option) is to include an additional cleaning and/or sanitizing step after storage and before the next use of the equipment. If this alternative is used, the measurement of both chemical and microbial residues should be performed at the end of this cleaning/ sanitizing step.

9) VALIDATION MAINTENANCE
Once a cleaning process has been appropriately validated, steps should be taken to help insure that the cleaning process remains consistent and in control. Steps that are taken to help assure this include regular monitoring, a change control system, training, and revalidation.
Monitoring
Change Control

Training
Training operators in the cleaning SOP is an important part of validation maintenance, particularly for manual cleaning methods. Training in a manual method should include a classroom discussion of the method, observation of the SOP being performed by a trained operator, and then demonstration of proficiency by performance of the SOP by the trainee. [17,7]

Revalidation
There are two aspects to revalidation of a previously validated cleaning process. First is revalidation upon any significant change. What is ‘‘significant’’ is a matter of professional judgment. However, a change in cleaning method, such as from manual cleaning to automated cleaning will generally require revalidation even though the cleaning agent and process parameters are the same. In essence this is not really revalidation but rather validation of a new cleaning process. The other aspect of revalidation is based on the evaluation of the consistency and control of a cleaning process on a regular basis to confirm that the process is still under control. The time of this periodic revalidation should be specified in a cleaning validation policy (such as in the cleaning validation master plan), and typically is every one or two years. Such a periodic revalidation involves an evaluation of the monitoring data, change control, cleaning process deviations, and quality records of products manufactured after the cleaning process. If the monitoring data is adequate, the change control is minor, any deviations have had attributable to corrected causes, and there have been no product quality problems possibly related to cleaning, then all this information is suggestive of a cleaning process that is still under control. In such a case it is possible to document such findings in a revalidation report with a conclusion that the cleaning process is still under control and that the original validation work is sill applicable. On the other hand, if the monitoring data show continual trends which require corrections, if numerous individual changes have been made (each of which was acceptable) but the overall cleaning process is now seen as significantly different, if deviations in the cleaning process have either not been attributable to a cause or the cause has not been corrected, and/or if there have been product quality issues related to the cleaning process, then such an investigation may result in a repeat of one or more PQ runs. In such a case, usually there will be some laboratory or pilot scale evaluations before PQ runs are performed. [4,17]

New Challenges in Cleaning Validation
Cleaning validation has been one of the most discussed topics in pharmaceutical industry in the past decade. When cleaning validation became a new requirement in the earlier 1990’s, most pharmaceutical firms focused their efforts on defining cleaning validation requirements, establishing acceptance criteria, and designing/conducting cleaning validation processes. As more firms completed their cleaning validation programs and began to share their experiences through publications and conferences in the mid to late 90’s, the focus of the efforts shifted to process improvement and efficiency enhancement for their cleaning validation programs. In the past few years, there were more discussions on cleaning validation maintenance programs. Recently, handling multiple cleaning validation programs became important due to company mergers and extensive contracting activities among the industry. It becomes increasingly important to expand the scientific capacity of a cleaning validation program to allow effective incorporation of multiple cleaning validation programs. The author believes that the challenges will continue to evolve and the ability to anticipate potential future challenges and proactively address these potential challenges by scientific and systematic approach is critical for the sustain ability of a cleaning validation program. [12]

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