PEER-REVIEWED

Impact of API Physicochemical Properties on Cleaning Method Design and Cleaning Validation

William R. Porter

ABSTRACT purpose of a cleaning method is to minimize cross- Physicochemical properties of active pharmaceutical contamination from previously manufactured product ingredients (APIs) and excipients used in the manu- when the subsequent product is to be manufactured facture of pharmaceutical dosage forms play a critical on cleaned equipment. Cleaning validation serves to role in the successful design of robust and validated demonstrate that the cleaning method can achieve cleaning processes. The development and validation this goal. of these methods requires an understanding of the Prevention of cross contamination between differ- solubility properties and resistance to degradation ent product lots manufactured on shared equipment is of formulation components, including both API and accomplished by using a validated cleaning procedure excipients. Knowledge and understanding of physi- (the method). The cleaning method should be devel- cochemical characteristics is critical to cleaning agent oped according to scientific and technical principles, selection, cleaning procedure design, worst-case com- be validated in designated conformance trials, be pound identification, and analytical method selection well controlled in performance, and be monitored and development. Much of the information needed and maintained throughout the product lifecycle. concerning solubility (i.e., hydrophilicity/lipophi- The cleaning method is validated by demonstrating licity, ionizability, surface activity, and temperature that remaining residue on the equipment surfaces effects) and degradation (i.e., hydrolysis, oxidation, is below a calculated acceptable residue level that photochemical reactivity) is routinely obtained dur- provides clean equipment that can be safely used for ing preformulation studies on new API candidates, subsequent manufacturing. or can be efficiently obtained at that time. Points Critical to the development of a reliable and to consider and questions to ask relating to physico- robust cleaning procedure is consideration of chemical property identification that are relevant to appropriate scientific and technical knowledge of cleaning are reviewed. the properties of the product residue to be cleaned. Fundamental knowledge of the physicochemical properties of the active pharmaceutical ingredient INTRODUCTION (API) and other formulation components is essential Development and validation of cleaning processes in this regard. Understanding the solubility and for equipment used in the manufacture of pharma- stability properties of the residue to be cleaned are ceutical dosage forms is critical to the assurance of vital areas of study. Without knowledge of solubility efficacy, safety, and quality of the final product. The and stability characteristics of the active drug and

ABOUT THE AUTHOR For more Author William R. Porter formerly served for more than 25 years as Pharmacist, Senior Pharmacist, Senior information, Pharmaceutical Scientist, and Associate Research Fellow in the Pharmaceutics group at Global Pharma- go to ceutical Research and Development, Abbott Laboratories, Illinois, USA. He may be reached by e-mail gxpandjvt.com/bios [ at [email protected].

gxpandjvt.com Journal of Validation Technology [Spring 2011] 87 PEER-REVIEWED

inactive residue to be cleaned, the following cannot cleaning a surface, at least some of the undesirable be determined: residue must be dissolved, emulsified, or suspended • A rational selection of cleaning agent cannot to some extent by the cleaning agent, which in most be made cases is fortified with additives to enhance the • A rational cleaning procedure cannot be solubilization process. Alternatively, alcohol may be developed required as a cleaning agent in some cases based on • Determination of the worst-case compound in favorable solubility of the API in alcohol. The follow- a cleaning matrix cannot be made ing is a review of the basic physicochemical concepts • A rational analytical testing of residues cannot that influence solubility. Several publications provide be accomplished. more detailed coverage of this topic (1, 2). The following topics related to solubility are briefly The above are fundamental to the development of discussed: cleaning methods and the conduct of cleaning valida- • Hydrophilicity/hydrophobicity (or lipophobicity/ tion. Solubility and stability properties are fundamen- ) tal areas of interest in pharmaceutical R&D, but may • Ionization and the effect of pH not be generally known to cleaning method devel- • Effect of temperature opers. However, in most pharmaceutical product • Surface activity development programs, much of the physicochemical • Liquid and semisolid product vehicle polarity property information needed to assist developers of • Impact of solubility on cleaning procedures and cleaning methods will have been obtained as part of cleaning validation. preformulation studies typically performed early in the development process. Those charged with devel- Hydrophilicity/Hydrophobicity oping cleaning methods may have to ferret out this (or lipophobicity/lipophilicity) information if knowledge management procedures Like dissolves like. Water has a high dielectric con- are not in place in their organization to assure avail- stant (i.e., a measure of its polarity, or ability to ability of information. Cleaning method development become oriented in space by application of an exter- specialists, as customers for preformulation informa- nal electric field). Substances that also exhibit high tion, may need to make their special needs known to polarity, such as table salt (an ionic substance) or those who actually conduct physicochemical property sucrose (an electrically neutral substance containing elucidation studies to ensure that the physicochemical many polar hydroxyl substituents) intermix well with data needed to support cleaning method development water molecules–they are hydrophilic (“water-loving”) is acquired in a timely and economical manner. Sub- molecules. These molecules form solutions in which mitting a special request for studies to be conducted molecules of the polar substance are dispersed in a sea just to support cleaning method development is not of water molecules stabilized by dipole-dipole, dipole- cost-effective and may delay development. It is essen- charge, or hydrogen bonding interactions. Substances tial that the cleaning method stakeholders understand that do not exhibit high polarity, such as animal what they need and expect from preformulation col- (e.g., glycerol esters of long-chain fatty acids), do not leagues and makes those needs known well in advance mix well with water. They are hydrophobic (“water- of the time the information is actually wanted. This hating”) molecules. There are only limited ways, other review addresses specific applications of fundamental than van der Waals’ forces, in which molecules having principles of solubility and stability as well as how this low polarity can interact with water molecules. The information applies to cleaning method development introduction of a hydrophobic nonpolar molecule and cleaning validation. into liquid water actually forces the water molecules to become more ordered and less random in their SOLUBILITY orientation, because opportunities for water molecules The solubility properties of an API are part of the to engage in stronger interactions, such as hydrogen fundamental physicochemical properties determined bonding, are reduced in the direction of the nonpo- in preformulation studies. Knowledge of these proper- lar solute. Nonpolar (greasy) substances dissolve ties is useful in the development of cleaning methods more readily in nonpolar (lipophilic—“-loving”) and in the approach to cleaning at the commercial . Conversely, polar substances have little manufacturing site. At some point in the process of affinity for nonpolar (i.e., they are lipophobic—

88 Journal of Validation Technology [Spring 2011] ivthome.com WILLIAM R. PORTER

“fat-hating”) and will tend to separate from fatty or though the parent substance from which they were nonpolar materials to form a new phase. derived is not. Substances that are weakly acidic in The determination of the relative hydrophilicity/ aqueous solution tend to be less soluble in acidic lipophilicity of new drug substances is critical to the cleaning media because the acidity of the cleaning development of new drug products and methods medium suppresses ionization of weak acids. Sub- for analyzing them, in addition to its impact on stances that are weakly basic in aqueous solutions cleanability. Conventionally, the affinity for a new tend to be less soluble in alkaline cleaning media API for polar and nonpolar media is represented by because the alkalinity of the cleaning medium sup- its octanol-water partition coefficient (3,4). Octa- presses ionization of weak bases. The manipulation nol-water partition coefficients are such important of cleaning solution pH is an easy tool for enhancing predictors of the behavior of chemical substances solubilization of troublesome residues. Lipophilic in solution that their determination is often one residues (e.g., from mixtures containing lubricants of the first activities performed in characterizing such as magnesium stearate) are often difficult to the physiochemical properties of a new API candi- remove from surfaces. Many commonly encountered date. Because partition coefficients vary by orders lipophilic substances are either weak acids or com- of magnitude, typically the base 10 logarithm of prised of materials that can undergo degradation the partition coefficient is reported (logP) as a mea- under conditions of extreme pH to form weak acids, sure of lipophilicity. An increase in logP from +1 so highly alkaline cleaning media tend to promote to +2 represents a 10-fold decrease in affinity for solubilization of such materials. For drugs that polar solvents (e.g., water) and a 10-fold increase in are weak bases, alkaline cleaning media can actu- affinity for nonpolar solvents (e.g., octanol). Many ally render them less soluble. If contamination of effective small molecule APIs typically have logP surfaces with a weakly basic API is problematic, an values in the range 2–3, and are, therefore, mod- acidic cleaner may improve cleanability. Measure- erately lipophilic and thus poorly soluble in water. ment of ionization properties of new APIs is one of In recent years, the trend has been for medicinal the first physicochemical properties determined in chemists to develop even more lipophilic new drug preformulation studies; it and lipophilicity are so candidates (logP > 4), which can pose problems for critical that in silico methods for predicting logP and designing effective cleaning procedures. Not only ionizability are increasingly used very early in the do these lipophilic APIs have poor water solubility drug discovery process (6). themselves, but frequently require incorporation of equally lipophilic excipients into formulations to Effect of Temperature provide effective drug delivery, thus compounding Temperature plays an important role in solubility the cleaning problem. and in the cleaning process. In most cases, solubility increases with an increase in temperature. In some Ionization and the Effect of pH cases, the increase is large; in others, the increase is The chemical structures of many APIs contain moi- minimal. For a few compounds, solubility actually eties that can dissociate when dissolved in water to decreases with an increase in temperature. These form positively- and negatively-charged ions. Ions effects may be explained by the physical interactions are far more polar than non-ionized substances and of the molecule of interest with the compared dissolve much more readily and to a greater extent to physical interactions of the molecule with others in water than the non-ionized form of the drug sub- of its own kind (i.e., in forming a crystalline solid). stance from which they originated. Thus, solution These properties must be known when developing a pH plays an important role in the dissolution and rational cleaning procedure, but may only be char- solubilization of many drug substances (5). Typi- acterized in a limited fashion during preformulation cal pharmaceutical excipients, on the other hand, studies. However, process chemists charged with rarely contain moieties that can ionize to any appre- developing efficient procedures for production of ciable extent in aqueous solution. However, some new APIs frequently conduct solubility studies as excipients, and many APIs, can undergo degrada- a function of temperature as part of their normal tion reactions under conditions of extremely low process optimization work, and should be consulted or extremely high pH, leading to the formation of to learn more about the effects of temperature on degradation products that may be ionizable, even solubility. gxpandjvt.com Journal of Validation Technology [Spring 2011] 89 PEER-REVIEWED

Surface Active Molecules dielectric constants. Semi-polar liquids are miscible As we have seen, polar solvents (like water) and non- with polar solvents and with non-polar solvents. Semi- polar solvents (like octanol) won’t stay mixed for long, polar liquids are often used in product development to even after vigorous physical agitation. The surfaces enable solution formulations. Semi-polar solvent like of each phase tend to actively repel molecules of the alcohol may be used in cleaning for highly insoluble other phase, leading to rapid phase separation when APIs or other troublesome formulation components. disruptive physical forces are removed. The molecules at the surface of adjoining phases interact preferen- STABILITY OR DEGRADATION tially with other molecules in the phase from whence Few substances can resist chemical transformation. they came rather than with their opposite numbers The stability properties of an API are part of the fun- in the adjoining phase. If a substance is added to a damental physicochemical properties determined in physical mixture of a polar and a nonpolar liquid preformulation studies. As development progresses that can reduce this surface activity (a surface-active into early formulation studies, additional stability agent, or surfactant), then it is possible to form an or degradation studies are conducted on prototype emulsion—globules of one liquid phase within the formulations or mixtures of the API with selected other liquid phase that remain physically stable for excipients to study how formulation components long periods of time. Surfactants are amphiphiles: one alter the stability of the API; these are often called portion (typically the larger portion) of the surfactant excipient compatibility studies. Fortunately, most molecule is nonpolar, while the (smaller) remainder API candidates must exhibit “reasonable” chemical is polar. Surfactants promote wetting, emulsifica- and physical stability in order for them to be devel- tion, and dispersion of suspended solids to enable oped and marketed, so the real challenge to cleaning cleaning. Surfactants generally enhance the ability method developers is to understand whether special of aqueous cleaning media to solubilize, emulsify, conditions to which the API and excipients may be or suspend less polar substances (7). Some APIs and exposed during cleaning operations are sufficiently formulation excipients are also surface-active and adverse to cause significant degradation that may may interact to form insoluble residues if mixed with impact ease of cleaning. a surface-active cleaning agent of the wrong sort. For Validation and compliance personnel must be aware example, lipophilic APIs containing a weakly basic of potential chemical and physical changes in the moiety capable of ionizing to form a cationic species product residues to be cleaned. Chemical stability could combine with an anionic surfactant (e.g., the refers to residue stability in the presence of oxygen, commonly used sodium lauryl sulfate) to form a salt light, heat, water, acid, base, metal ions, etc., any or all that may have poor water solubility, thus not only of which may impact pharmaceutical product residues reducing the effectiveness of the cleaning agent but remaining on manufacturing equipment. Physical sta- also producing a new hard-to-clean residue. bility refers to changes where the chemical molecular structure of a solid remains the same, but the physical Liquid and Semisolid form and physical properties of a solid may change. Product Vehicle Polarity This is relevant to cleaning because properties that Pharmaceutical liquid and semisolid liquid products may change include solubility, hygroscopicity, chemi- contain vehicles of widely varying polarity. In general, cal stability, and other properties. Solid phase transi- water is a polar vehicle with a high dielectric constant tions can affect cleanability if the result is conversion and is a good solvent for polar hydrophilic molecules. of a more water-soluble solid form to a less water- At the other extreme are non-polar, low dielectric soluble form. Unlike chemical reactions, which can constant vehicles such as mineral or petrolatum destroy an API and convert it to a degradation product that might be used in topical ointment products. that may not be detectable using an analytical method These molecules are good solvents for hydrophobic designed to quantify the API, physical changes usu- non-ionizable drugs. Between polar solvents such ally just affect the ease or difficulty of removing the as water and non-polar solvents such as octanol are API from the surface. An understanding of how APIs the semi-polar solvents. Ethanol is representative of and excipients may degrade or undergo physical form this category of solvent, which also includes liquids changes during cleaning is essential to the develop- such as propylene glycol and low molecular weight ment of rugged and reliable cleaning processes (8–11). polyethylene glycols. These liquids have intermediate Furthermore, this understanding is essential to selec-

90 Journal of Validation Technology [Spring 2011] ivthome.com WILLIAM R. PORTER

tion and development of the appropriate analytical Effect of temperature. The rate of a reaction is method for use in cleaning validation testing. The affected by temperature. The Q10 rule, attributed to techniques for elucidating the effect of cleaning sys- pioneering physical chemist Jacobus H. van’t Hoff, tems on API stability in formulated products are not states that the velocity of a chemical reaction increases all that different from experimental methods used in approximately two- to threefold for each 10 °C rise preformulation studies of the degradation potential of in temperature. His student, Svante Arrhenius (12), the pure API. Indeed, similar experiments could be developed this into a more formal theory relating the performed to compare alternate cleaning strategies. rate of degradation to absolute temperature: The following topics related to stability are briefly discussed: Ea ln(kg,T) = ln (Ag)− • Kinetics of chemical degradation RT • Common degradation mechanisms Here k is the rate constant for reaction mechanism • Physical stability–phase transformations g, A is a constant known as the Arrhenius frequency • Applications of stability to cleaning procedures factor (the limiting rate as the absolute temperature T and cleaning validation. is increased to infinity) that is also characteristic for

mechanism g. Ea is the factor by which the reciprocal Kinetics of Chemical Degradation of the absolute temperature T must be multiplied to Chemical degradation reactions of pharmaceuticals estimate the degradation rate and R is the universal and excipients follow the well-established principles gas constant of physical chemical theory. Knowledge of chemical kinetics (8–11). During the course of a of Ea is important because when degradation reactions chemical reaction, the concentrations of reactants are known to occur, they will be accelerated when and products change with time until the reaction high temperature cleaning is conducted. Although either reaches completion or equilibrium. The con- the design of cleaning methods requires the under- centrations of the reactants decrease over time, while standing of degradation reactions in solution, what those of the products increase. The rate of a reaction happens to solid dosage forms prior to cleaning is also can be represented either by the decreasing change important. Advances in this field permit fairly rapid in the concentration of a reactant or the increasing estimation of degradation in solids using accelerated change in the concentration a product with respect conditions (13). Reactions with larger Ea values are to time. more sensitive to changes in temperature. As quality- Reaction mechanisms. Reaction mechanisms are by-design (QbD) initiatives become better established, well known and explained in discussions of chemical information on degradation pathways and their sen- kinetics. An overall reaction may contain a number sitivity to temperature effects are increasingly being of elementary reactions. A complete scheme of these studied earlier in the pharmaceutical development elementary reactions represents the actual path of process. However, it may be the case that the design a reaction and is called the mechanism of the reac- of cleaning methods might be the first instance in new tion. Among the elementary reactions comprising an product development where this information becomes overall reaction, one of these steps usually proceeds critical to quality (CtQ). If so, consider incorporating with the slowest rate. This slowest step is called the studies of API degradation in prospective cleaning rate-determining step of a reaction and determines media into preformulation studies if these experi- the rate of the overall reaction. Once the reaction ments are not already being performed. Minimally, mechanism is known, and the rate-determining step the effect of solution pH on degradation rate should is identified, the expression of the overall rate of the be studied. reaction may also be readily derived. Reactions may be zero order, first order, second order, etc. depending Common Degradation Mechanisms on molecularity of the reaction. Degradation reactions Both APIs and excipients can degrade when exposed of API residues with cleaning agents are bimolecular, to environmental stressors. During cleaning opera- but appear to be first order because the concentration tions, pharmaceutical product residues are exposed of the API is limited and the cleaning agent is present to water (and possibly to extremes of pH), air, and in great excess. It is thus called a pseudo first order light (14-18). Water promotes hydrolysis of labile reaction with respect to the API present in limited functional groups in both APIs and in some excipi- amounts. ents where such groups are present. Air can cause gxpandjvt.com Journal of Validation Technology [Spring 2011] 91 PEER-REVIEWED

oxidation, which is facilitated by the high surface remaining API. However, although many oxidation area of residues that contaminate equipment surfaces. products are more water-soluble and easier to rinse Exposure to light can promote photolytic degradation, away as a consequence, this is not always true. Spe- especially because residues are present as thin layers cific analytical methods designed to measure API on contaminated equipment surfaces. Components may show the “clean” surface to be free of API itself, of cleaning media added to control pH can catalyze while oxidation products produced in the decon- hydrolysis reactions. Corrosion products generated tamination process remain undetected. either within the manufacturing process or during Photolysis. According to the Grotthuss-Draper cleaning operations can also catalyze reactions, par- law, no photochemical reaction can occur unless ticularly oxidation reactions. light is absorbed (20, 21). The relevant radiation Hydrolysis. Hydrolysis is by far the most com- bands that are most likely to be problematic to phar- monly encountered drug degradation mechanism maceuticals are visible light (~ 400–800 nm) and both in solution and also in the solid state. Many drug ultraviolet (UV) light (~ 200–400 nm). Sunlight molecules contain derivatives of functional groups in the wavelength range of 200–280 nm (UV-C such as carboxylic acids that are readily cleaved by range) is effectively absorbed by molecular oxygen water or hydroxylic solvents. Hydrolysis of such deriv- and ozone in the upper atmosphere and is, there- atives can occur both in solution and in the solid state fore, not considered to be important for photolytic in the presence of water. In particular, the presence degradation of drugs, although many organic sub- of hydrogen or hydroxyl ions present at low or high stances do absorb strongly in this wavelength range. pH catalyzes hydrolytic reactions. Because cleaning Borosilicate glass also effectively blocks exposure media typically are formulated at extremes of pH to to UV-C light. Ordinary soda-lime window glass facilitate removal of excipient residues, the degrada- further blocks radiation in the 280–315 nm (UV- tion of APIs containing functional groups susceptible B) range. Photochemical degradation is typically to hydrolysis should be anticipated. studied using artificial lighting to mimic exposure Oxidation. Oxidation presents an important to indoor sunlight in 315–400 nm (UV-A) range, and drug degradation pathway and is second only to so exposure to higher energy UV radiation (200–315 hydrolysis. To some extent, the potential for oxida- nm) is often deliberately blocked (e.g., by use of a tive degradation can be predicted theoretically (19). soda-lime glass filter). However, manufacturing Although its significance to drug stability has been facilities often are equipped with artificial light recognized, the study of oxidative stability has not sources that may emit UV radiation in the UV-B been well developed until more recently, partially region (e.g., high-pressure mercury arc lamps) or due to its complicated nature. Many pharmaceuti- UV-C region (e.g., quartz tube germicidal lamps) cal compounds contain amine functional groups. that can induce photochemical degradation not Amines are known to be prone to oxidation. Oxi- detected in ordinary stress tests. All organic com- dation of amine-containing APIs by atmospheric pounds containing aromatic rings (which include oxygen can occur during hold times when residues most APIs) absorb radiation in the UV-C range. If are left on equipment prior to cleaning. Reactions equipment surfaces contaminated with residues with atmospheric oxygen are particularly likely to to be removed by cleaning were exposed to such occur when equipment is first rinsed with plain water radiation sources, unexpected degradation products and then allowed to sit for some time before final could be produced. cleaning with a formulated cleaning medium. Damp residues will absorb oxygen from the air and solvent- Physical Stability: Phase Transformations mediated oxidation reactions can then proceed while Physical stability refers to the ability of a solid phase the equipment is waiting for final cleaning. Exposure to resist transformation under various conditions. of drug product residues containing APIs having Although in some cases tautomerism may be involved, amine moieties to oxidizing agents such as com- this section encompasses phase transitions where the mercial bleach (sodium hypochlorite) or hydrogen chemical molecular structure remains the same (22, peroxide frequently will result in partial or total 23) but the physical form changes (polymorphism). destruction of the API. Oxidation is frequently intro- Many substances have two or more distinct solid forms duced deliberately in cleaning processes as a final (polymorphs). Elemental carbon, for example, is most decontamination step to assure destruction of any stable at ordinary temperatures and atmospheric pres-

92 Journal of Validation Technology [Spring 2011] ivthome.com WILLIAM R. PORTER

sure as graphite, but under conditions of high pressure, equipment used in one process may fail when used to carbon can form another solid phase—diamond. clean equipment used in a different manufacturing Various solid forms of a chemical entity may have process. That different processes affect cleanability in different physicochemical properties. For example, different ways should not be cause for astonishment; while diamond is an excellent conductor of heat, it the discussion above may help us in understanding is an electrical insulator; graphite, on the other hand some of the underlying reasons for these differences. conducts electricity readily. Some of these properties are relevant to pharmaceutical development, such as CLEANING AGENT SELECTION AND solubility or dissolution rate, hygroscopicity, melting CLEANING PROCEDURE DEVELOPMENT point, chemical stability, etc. Extensive efforts are The cleaning method for the product residue should invested early on into the selection of an optimum be consistent with the physicochemical properties— solid form as an API for downstream development, solubility and stability—of the residue to be cleaned. typically as part of preformulation and chemical In some cases, these properties can be used advan- process development studies. The understanding of tageously to facilitate cleaning. For example, a basic the physical stability of the selected API solid form drug substance may be easily cleaned by use of an is minimally necessary to realize the benefit of the acidic cleaning agent. In fact, simply adjusting the selected solid form, to ensure control during the pH of a soaking liquid may essentially accomplish manufacturing processes, and ultimately to assure cleaning without use of a complex cleaning agent. the quality of finished products containing the API. In some formulations, while the active ingredient is Solid phase transitions can affect cleanability if the the most critical compound to be cleaned regarding result is conversion of a more water-soluble solid form carryover to subsequent product, inactive ingredi- (e.g., a salt, amorphous form, unstable polymorph) ents such as colorants may be the most troublesome to a less water-soluble form (e.g., thermodynamically residues to clean. It may be more difficult to remove most stable crystalline polymorph of non-ionized par- colored residue from the equipment surface than it is ent form of API, hydrated form of anhydrous API, etc.). to remove active drug. If this is the case, development Some changes can be induced by the cleaning agents of a cleaning method for the colored excipient will be used (e.g., precipitation of the free base of an API that the primary objective in cleaning procedure develop- is the salt of an amine drug by an alkaline cleaning ment; this method must also remove active drug resi- agent, formation of an insoluble salt by exposure to due. There must be good understanding of the stability an incompatible ionic surfactant, etc.). Such changes properties of the compound of interest. For example, can sometimes make the API harder to remove from protein molecules may be hydrolyzed by alkaline the surface. cleaning agents to form amino acid fragments, which As a result of exposure to the various forces (e.g., are usually more soluble and easier to clean than the heat, pressure, dissolution, drying) during manufac- parent molecule. If the compound of interest degrades turing processes, APIs and excipients may be con- to an insoluble compound, the cleaning method must verted to solid forms that differ in rate and extent consider the solubility properties of the degradation of solubilization in cleaning media. The common product as well as the solubility properties of the par- lubricant, magnesium stearate, is a dihydrate at ordi- ent compound. Likewise, a cleaning agent that would nary humidity and ambient temperature, but when cause an API or excipient to change physical form heated in a dry environment, it loses water and con- and become less soluble would likely make cleaning verts to an anhydrous solid form with different solu- more difficult—and the cleaning procedure should bility properties. When exposed to moisture, on the necessarily be designed to address the newly formed other hand, it converts to a trihydrate form, again, insoluble residue. For example, a tablet formulation with different solubility properties. Granulation and containing magnesium stearate as a lubricant may compaction greatly reduce surface area, which dimin- become more difficult to remove from equipment ishes the overall dissolution rate. Other processes surfaces treated with an acidic cleaning agent, as the may lead to formation of metastable amorphous or magnesium stearate would be converted to stearic thermodynamically less stable polymorphic solid acid. Some compounds—active drugs, degradation forms with higher solubility or higher surface area products, or inactive excipients such as colorants—are or both. Thus, cleaning procedures that were tested so insoluble in water that a non-aqueous solvent such and found to be effective for removing residues from as ethanol is preferred for cleaning. gxpandjvt.com Journal of Validation Technology [Spring 2011] 93 PEER-REVIEWED

DETERMINATION OF WORST-CASE the most difficult-to-clean degradation products COMPOUND IN A CLEANING MATRIX in order to appropriately compare the API and its Multiproduct manufacturing facilities often use a degradation products to the model hard-to-clean matrix approach for cleaning validation. In this compound. In cases of protein product cleaning, a approach, cleaning validation of a worst-case prod- non-specific analytical method such as measurement uct covers the cleaning of other products that are of total organic carbon (TOC) is often used to verify less difficult to clean. The determination of the equipment cleanliness because the parent molecule worst-case product is based in part on the solubil- may be completely destroyed in the high pH cleaning ity of the compound of interest. Thorough and process. The use of non-specific methods for small complete understanding of solubility, including molecule APIs could, if practicable, eliminate many solubility in acid, alkaline, and neutral pH should of the concerns with respect to chemical and physical be known. Also, solubility in the cleaning agent fate discussed here. should be known. An ionizable compound that is highly soluble in an alkaline cleaning agent can- RECOMMENDATIONS not be claimed to be a worst-case compound just Validation and compliance personnel should be sure because it is mostly non-ionized and poorly soluble that solubility properties of the residues that must in pure water. Solubility in water is truly irrelevant be cleaned from manufacturing equipment are well when the solubility of a compound exhibits signifi- known and understood. Solubility in various sol- cant pH-dependency or is solubilized in cleaning vent classes should be known. Solubility as a func- by micellization or emulsification. If the residue to tion of pH should be known. The usual pH range be cleaned is a degradation product of the original for such studies is from pH 1 to pH 8, the normal active drug, its solubility as a function of pH and in human physiological pH range, and is covered in potential cleaning agent solutions must be known typical preformulation studies. However, extending to correctly determine the worst-case compound in the pH range to pH 12 is useful for cleaning valida- a cleaning matrix. This assessment cannot be made tion because alkaline surfactant cleaners at this pH without knowledge of the stability properties of the are commonly used in pharmaceutical manufacturing compound of interest. facilities; you may need to communicate your need for this information to preformulation scientists if it ANALYTICAL METHOD is not being provided to you routinely. The effect of FOR CLEANING VALIDATION temperature on solubility at optimum cleaning pH Care must be exercised in selection of the analytical should be known. Further, extending these solubility method for cleaning validation to assure that the studies to include surfactant solutions at or above the method quantifies the “worst case” residue, whether critical micelle concentration is even more relevant that may be a new physical form for the API itself to cleaning. Because these special needs of cleaning or a degradation product. For example, an analyti- method stakeholders may not be routinely addressed cal method highly selective and specific for the API in preformulation studies, be sure to communicate may not, in fact, be the best choice. Is the parent your requirements early and clearly. API the actual remaining moiety on the equipment Many hypothetical degradation reactions have surface after cleaning with highly acidic or highly been discussed in this review. In any real product alkaline pH? What happens to the target molecule development process, the degradation processes that under these rigorous and potentially reactive con- are relevant to a particular drug product are typically ditions? It may be more appropriate to develop an identified in laboratory studies well in advance of the assay for both the parent molecule and degradation need to develop a cleaning process for manufacturing products or degradation products alone—or even equipment, either in preformulation studies or dur- to use a nonspecific method—in these situations. ing the development of stability-indicating analyti- When matrix approaches to cleaning are used to cal methods. Personnel responsible for developing evaluate the effectiveness of cleaning, it is important cleaning processes should communicate their need to understand the solubility properties not only of for information on how components of the drug the parent API, but also the properties of any new product might degrade during potential cleaning physical forms that may be produced by the clean- processes to scientists and engineers engaged in those ing process as well as the solubility properties of earlier development activities. Appropriate stress

94 Journal of Validation Technology [Spring 2011] ivthome.com WILLIAM R. PORTER

degradation experiments can easily be incorporated then the analytical method must be designed so into these earlier product development activities as to show that API degradation products are also with little additional cost or expense. Appropriate removed by cleaning. This discussion identifies some stability-indicating analytical methods will have of the factors that have the potential to complicate been developed that can be modified to support the development of a validated cleaning procedure. cleaning studies. Environmental conditions for This is not to say that all, or even any, of the changes handling samples that could be problematic will in material properties suggested will occur in your have been identified. Potential incompatibility with manufacturing process; however, when unexpected cleaning agents (pH, type of surfactant) will have results are obtained, one or more of the chemical been recognized. However, the designer of the clean- or physical processes described herein may likely ing process, by understanding the types of chemical be the root cause of the difficulty. The resolution degradation reactions that can potentially occur, will of problems encountered during the investigation be better able to communicate with and influence of cleaning failures may lead to cleaning process the type of exploratory work performed by colleagues improvements. Careful consideration of potential involved with earlier phases of product development, causative factors outlined in this discussion in seek- where chemical reactivity is typically studied. For ing resolution of cleaning challenges can lead to example, stability as a function of pH should be process changes that greatly improve not only the known. Stability at pH 2 and pH 12 is particularly cleaning process, but also the scientific and technical relevant for cleaning validation because acid or alka- basis for the cleaning program. line surfactant cleaners at these pHs are commonly used in pharmaceutical manufacturing facilities. The effect of temperature at optimum cleaning pH REFERENCES should be known. Stability as affected by air (oxida- 1. Yalkowsky, S. H., Solubility and Solubilization in Aque- tion) and light (photolysis) is also relevant because ous Media, Oxford University Press, New York, 1999. dried residue may be exposed to air and light for 2. Rao, V. M.; Sanghvi, R.; Zhu, H., “Solubility of Pharma- extended periods during the time between end of ceutical Solids,” In: Developing Solid Oral Dosage Forms: manufacturing and start of cleaning. Pharmaceutical Theory and Practice, Qiu, Y.; Chen, Y.; Zhang, G., Liu, L.; Porter, W., Elsevier, New York, 2008. CONCLUSIONS 3. Hansch C., Leo A., “The Hydrophobic Parameter: Mea- A basic understanding of the chemical and physical surement and Calculation,” Exploring QSAR: Fundamen- properties of the materials used to produce pharma- tals and Applications in Chemistry and Biology, American ceutical products, coupled with an understanding Chemical Society, Washington, DC, 1995. of how processing conditions can lead to changes 4. Hansch C., Leo A., Exploring QSAR: Hydrophobic, Elec- in these properties through chemical degradation tronic and Steric Constants, American Chemical Society, or physical form transformation, should help us Washington, DC, 1995. to devise cost-effective, appropriate, rugged, and 5. Sinko, P., Martin’s Physical Pharmacy and Pharmaceutical reliable cleaning methods. Knowledge of solubility Sciences, 5th Ed., Lippincott Williams & Wilkins, Phila- and stability properties are especially relevant in delphia, PA, 2005. this regard. Knowledge of solubility and stability 6. van de Waterbeemd, H., Gifford, H., Admet In Silico properties of residues to be cleaned will enable a Modelling: Towards Prediction Paradise? Nature Rev rational choice of cleaning agent and development Drug Discovery, 2:192–204, 2003. of a rational cleaning procedure. Without knowl- 7. Verghese G, Kaiser N., “Cleaning agents and cleaning edge of the physical properties of the residue to be chemistry,” In: Pluta PL., ed, Cleaning and Cleaning Vali- cleaned, determination of the worst-case compound dation for the Pharmaceutical and Medical Device Indus- in a cleaning matrix cannot be made. In particular, tries, PDA, Bethesda, MD pp. 103–122, 2009. this understanding is especially valuable to the ana- 8. Carstensen, J. T., Drug Stability Principles and Practices, lytical chemist charged with the responsibility for Second Edition, Revised and Expanded, Marcel Dejk- developing methods for the purpose of demonstrat- ker, Inc., New York, NY, 1995. ing that surfaces have been sufficiently clean and 9. Yoshioka, S., Stella, V. J., Stability of Drugs and Dosage that no contaminating residues of API can be found. Forms, Kluwer Academic/Plenum Publishers, New York, If the API can degrade during the cleaning process, 2000. gxpandjvt.com Journal of Validation Technology [Spring 2011] 95 PEER-REVIEWED

10. Baertschi, S. W., Pharmaceutical Stress Testing; Predicting 18. Connors, K. A., Amidon, G. L., and Stella, V. J., Chemi- Drug Degradation, Boca Raton: Taylor & Francis, 2005. cal Stability of Pharmaceuticals. A Handbook for Pharma- 11. Zhou, D.: Porter, W.; Zhang, G., “Drug Stability and cists, 2nd ed. John Wiley & Sons, Inc., New York, p 64, Degradation Studies,” Developing Solid Oral Dosage 1986. Forms: Pharmaceutical Theory and Practice, Qiu, Y.; Chen, 19. Reid, D. L., Calvitt, C. J., Zell, M. T., Miller, K. G., and Y.; Zhang, G., Liu, L.; Porter, W., Elsevier, New York, Kingsmill, C. A., “Early Prediction of Pharmaceutical 2008. Oxidation Pathways by Computational Chemistry and 12. Arrhenius, S. A. Über die Reaktionsgeschwindigheit Forced Degradation,” Pharm. Res., 21, 1708-1717, 2004. bei der Inversion von Rohrzucker durch Saüren. [On 20. Turro, N. J., Modern Molecular Photochemistry, University the reaction rate for the inversion of sucrose by acids], Science Books, Sausalito, CA, 1991. Z Physik Chem 1889;4:226–248. 21. Tønnesen, H. H., Photostability of Drugs and Drug Formu- 13. Waterman, K. C.; Carella, A. J.; Gumkowski, M. J.; Lu- lations, 2nd ed. CRC Press: Boca Raton, Florida, 2004. kulay, P.; MacDonald, B. C.; Roy, M. C.; Shamblin, S. L., 22. Ostwald W., “The formation and changes of solids,” Z “Improved Protocol and Data Analysis for Accelerated Physik Chem 1897;22:289–330. Shelf-Life Estimation of Solid Dosage Forms,” Pharma- 23. Verma AR, Krishna P., Polymorphism and Polytypism in ceutical Research, 24(4): 780–790, 2007. Crystals, Wiley, New York, pp. 15–30, 1966. JVT 14. Connors, K. A., Amidon, G. L., and Stella, V. J., “Chemi- cal Stability of Pharmaceuticals,” A Handbook for Phar- ARTICLE ACRONYM LISTING macists, 2nd ed. John Wiley & Sons, Inc., New York, p API Active Pharmaceutical Ingredient 19., 1986. CtQ Critical to Quality 15. Connors, K. A., Chemical Kinetics: The Study of Reaction QbD Quality by Design Rates in Solution, Wiley-VCH Publishers, New York, p TOC Total Organic Carbon 191, 1990. UV Ultra Violet 16. Carey, F. A., and Sundberg, R. J., Advanced Organic Chemistry. Part A: Structure and Mechanisms, 4th ed., Plenum Press, New York, 2000. 17. March, J., Advanced Organic Chemistry: Reactions, Mecha- nisms, and Structure, 4th ed., John Wiley & Son, New York, 1992.

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