David W. Osborne, PhD, is Chief Scientific Officer and Founder, Independent Derm Solutions, LLC, 4215 Creekside Court, Fort Collins, CO 80525.

David W. Osborne

	In recent years, many topical probiotic personal care products have been launched into the market (1). In an August 2016 review for 

 (2), dermatologist Patricia Farris concluded, “The studies reviewed suggest that topical prebiotics, probiotics, and bacterial cell lysates do provide demonstrable skin benefits …At this time, it appears that more studies are warranted to determine if these products are really worth the hype.” These scientific reviews are quick to point out that well-crafted, vehicle-controlled clinical trial results are not generally available for topical semisolids containing live microorganisms. One reason that topical probiotic therapies have not advanced beyond the personal care “post-marketing surveillance regulatory environment” into the controlled clinical trial “new drug approval regulatory environment” is the difficulty in reconciling FDA microbiological requirements for a product containing live microorganisms. More specifically, how can a topical suspension containing more than 50,000 colony forming units (CFU) of probiotic active pharmaceutical ingredient (API) pass 

 <61>) (3), tests for specified organisms (

 <62>) (4), and antimicrobial preservative effectiveness (

	Two case studies are being presented here to explore the strategy of adequately preserving the formulation, but using a preservative of sufficiently narrow spectrum to maintain viability/potency of the probiotic active. The first case study uses a probiotic strain of 

 is a lipophilic, gram-positive anaerobic bacillus that resides in the pilosebaceous unit of human skin. Hundreds of different strains of 

 exist. The lipases, proteases, and hyaluronidases secreted by certain strains of 

injure the lining of the pilosebaceous unit and activate production of proinflammatory cytokines that in turn lead to acne vulgaris. Other strains of 

 produce no inflammatory response and thus do not induce the symptoms of acne vulgaris. One of these non-inflammatory strains of 

 has been chosen to be used as an “active ingredient” in a topical formulation product. In the second case study, the microorganism is a bacteriophage (phage), which is a virus that infects and replicates within a bacterium, ultimately causing bacterial death. The phage used in this study was isolated from the follicular casts obtained from volunteers with facial comedones. Bacteriophages were identified and isolated from the comedones and were then propagated using an amplification process and plated against different 

strains to determine breadth of efficacy to assure the selected phage was suitable to infect and eradicate pathogenic (inflammatory) 

	Formulating a living microorganism is fundamentally different from formulating a small-molecule active topical product. Because the 

probiotic or phage products will be dosed as suspensions, active solubility, solvent compatibility, and penetration across the 

 do not factor in to the development of a topical probiotic. In contrast, the aqueous probiotic formulation does require that pH and osmolality be adjusted to values that assure a favourable environment for the microorganisms to remain viable. In these two case studies, eight different formulations containing preservatives were tested for live microorganism viability over six weeks after compounding.

 (probiotic bacterial active) and phage that attacks pathogenic 

(microbiome editor) were provided by Phi Therapeutics. Two gelled aqueous products were made with the intent of formulating cosmetically elegant products: hydroxyethyl cellulose (HEC) at 1.5% w/w and polyacrylic acid polymer or carbomer (Carbopol 980, Lubrizol) at 0.75% w/w, both titrated with propylene glycol until isosmotic (~285 mOsm/k). Both gels were prepared with the following preservative systems: preservative free, methylparaben (0.1%) and propylparaben (0.02%), phenoxyethanol (1.0%), and potassium sorbate (0.2%). In addition, two solution products were made: an 80:20 water:propylene glycol blend (w/w) and an 80:20 water:ethanol blend (w/w). Both solution blends were considered self-preserving. The pH of all the products were taken, but no pH modifiers were added. Active viability and stability testing were conducted every two weeks after addition of active microorganism by diluting the formulated products to a known concentration of active microorganisms and plating them out. 

 concentration was calculated using diluted growth promotion plating and back calculating; the number of phage was calculated by plating the dilutions onto bacterial lawns and looking for the presence of kill zones.

	When added individually to the probiotic formulations, the parabens, phenoxyethanol, and potassium sorbate completely deactivated the product gelled with HEC or Carbopol by more than 99.95% within the first four weeks of compounding (see 

, only the 20% propylene glycol solution was reasonably tolerated. The 20% propylene glycol solution initially lost 90% activity at two weeks, but remained at a consistent level of activity from two to six weeks. The 20% ethanol and the Carbopol gelled water (non-preserved) products lost their potency by more than 99.95% within the first four weeks of compounding with the HEC gelled water (non-preserved) product performing no better than 20% propylene glycol product.

	The parabens, phenoxyethanol, and potassium sorbate in isotonic HEC formulations did not deactivate the phage six weeks after compounding. Formulating the phage with ethanol or propylene glycol up to 20% solvent did not have any effect on phage activity (see 

, however, the use of a negatively charged polymeric gelling agent (polyacrylic acid polymer) did deactivate the phage by about 95% two weeks after compounding and caused more than 99.95% loss in phage titer by four weeks.

	The basis for microbial enumeration testing (

 <62>) and antimicrobial preservative effectiveness (

 <51>) of topically applied non-sterile pharmaceutical products is the statement in US 21 

 211.113(a) that “Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed” (6). It should be noted that a topical probiotic product should not have greater difficulty in passing 

 <62> than topical products containing non-living actives. For topical probiotics, the living microorganism active is not “objectionable” and thus is not required by 

 <61> to be below 1000 CFU. Likewise, the absence of pathogens such as 

 <62> is necessary for the safety of any topically applied pharmaceutical. It is passing antimicrobial preservative effectiveness testing (

 <51>) that is the biggest hurdle to the development of a topical product containing a living microorganism as the active.

strain used in the first case study, only the addition of 20% propylene glycol was reasonably tolerated by the living microorganism active. The parabens, phenoxyethanol, potassium sorbate, and ethanol, when added individually to the probiotic formulation, deactivated the product by more than 99.95% within four weeks of compounding. The 20% propylene glycol liquid initially lost 90% activity at two weeks, but remained at a very consistent level of activity from two weeks through to six weeks. While a certain segment of the probiotic active appears susceptible to the cell membrane function interference exerted by a glycol, sufficient quantities of viable probiotic remain to manufacture an efficacious topical product. Blending propylene glycol with other glycols to optimize antimicrobial activity has been an area of active research within the field of dentistry (7). The results of the first case study, combined with the literature concerning the bactericidal activity of propylene glycol, indicate that addition of glycols to a fluid suspension of probiotic 

 is a reasonable development strategy for complying with 21 

	As expected, the phage was more resilient to the addition of preservatives to the formulation. Addition of ethanol to the formulation did not appear to have any effect on the phage. The parabens, phenoxyethanol, potassium sorbate, and propylene glycol did not appear to deactivate the phage six weeks after compounding. The use of a negatively charged polymeric gelling agent did deactivate the phage by approximately 95% two weeks after compounding and caused more than 99.95% loss in phage titer by four weeks. Obtaining a preserved bacteriophage probiotic topical gel is possible provided that an uncharged gelling agent such as HEC is used as the thickener.

	The phage has the capacity to tolerate a wide range of typical pharmaceutical preservatives, and it appears possible to formulate a cosmetically elegant final product if a nonionic gelling agent (such as HEC) is used. However, formulating a final product containing the probiotic 

 will be challenging, and certain amounts of care will need to be taken in working with the bacteria and choosing the best method of preserving the final product. Nonetheless, bacterial levels in the 20% propylene glycol aqueous solution have been relatively stable from weeks 2–6, indicating that this is a reasonable development strategy. From the results obtained from these two case studies, it can be concluded that it is possible to formulate a preserved topical product containing living microorganisms.

	1. M-CJ Huang and J. Tang, “Probiotics in Personal Care Products,” 

http://dx.org/10.7243/2052-6180-3-5 (2015).
	2. P.K. Farris, “Are Skincare Products with Probiotics Worth the Hype?” 

 Chapter <61> “Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests” 

 (US Pharmacopeial Convention, Rockville, MD, 2018), p. 5965.
	4. USP, 

 Chapter <62> “Microbiological Examination of Nonsterile Products: Tests for Specified Organisms” 

 (US Pharmacopeial Convention, Rockville, MD, 2018), p. 5971.
	5. USP, 

Chapter <51>, “Antimicrobial Effectiveness Testing” 

 (US Pharmacopeial Convention, Rockville, MD, 2018), p. 5959.
	

 Title 21, 211.113(a)
	7. T.M. Nalawade, K. Bhat, and S.H.P. Sogi, 


	Vol. 42, No. 3
	March 2018
	Pages: 32–36

	When referring to this article, please cite it as J. Carbol, et al., "Formulating Topical Products Containing Live Microorganisms as the Active Ingredient," 

	Jason Carbol is manager of Chemistry, Manufacturing, and Controls at Dow Development Laboratories (DDL), a division of Symbio, jcarbol@dowdevelopmentlabs.com; Pia Isabel Tan was a 2017 Dow Development Institute Intern who is currently a biochemistry major at UCLA; Yug Varma, PhD, is CEO at Phi Therapeutics; and David W. Osborne, PhD, is executive fellow at Dow Development Institute and senior vice-president of Product Development at Arcutis.

Articles

Case studies compare efficacy testing of preservatives for topical formulations with probiotic actives.

Formulating Topical Products Containing Live Microorganisms as the Active Ingredient

	Peer-Reviewed:
	Submitted: Jan. 8, 2016. Accepted: Jan. 28, 2016.  

Quality by design (QbD) is a scientific and risk-based approach to product development that begins at the product concept stage. This article will clarify reasonable expectations for the responsibilities of topical product formulation developers and for excipient suppliers regarding the information and samples for experiments needed for QbD.

As noted in Part I of this series (1), modern quality management techniques framed in terms of pharmaceutical regulatory concepts have been collectively called quality by design (QbD). QbD can be defined as a scientific, risk-based, holistic, and proactive approach to pharmaceutical product development. It begins at the product concept stage and is applied throughout development and into commercialization.

	The pharmaceutical industry is embracing QbD for topical products for both new drug application (NDA) and abbreviated NDA (ANDA) products. Recent publications (2–4) specific to topical dermatological products have been useful in providing guidance to development scientists that manufacture topical pharmaceutical products. QbD is truly the new paradigm in topical product development and is also being applied to topical products that have been on the market for many years.

	The goal of Part II of this two-part series is to review reasonable customer expectations regarding excipient information and sample requests. When the product development scientist implements the QbD approach, significant excipient questions are raised that seldom were considered during the old “quality-by-testing” paradigm. Excipient suppliers are being asked to more extensively characterize their materials and to supply material that is at the edge of the vendor specification. Just as in Part I, this discussion will be limited to topical dermatological preparations (both NDA and ANDA) that are meant to be locally active.

	Terms commonly used to classify product similarity when discussing design for equivalence are defined as follows:

		Q1 means that test and reference products have the same components.

		Q2 means that test and reference products have the same components in the same concentration.

		Q3 means that test and reference have the same components in the same concentration with the same arrangement of matter (microstructure). Structural similarity is established by comparisons between test and reference product of physicochemical characteristics, such as drug particle size, spreadability, viscosity, pH, and drug concentration in aqueous phase. Functional similarity is established by comparisons between test and reference product using in-vitro drug release testing (4).

	The meaning of being “the same” as defined in Q1 and Q2 is discussed as follows. A difficulty for the topical semisolid formulator is that some of the excipients used for pharmaceutical products are not compendial but are commonly used in cosmetic products. Thus, dozens of different grades of certain excipients are available for use that will have the same name. Molecular purity of an excipient, such as stearic acid, may range from 50% for food grade to over 98% for a high-purity grade used as a lubricant in pharmaceutical tableting. Verification of the molecular purity of the “same” excipient from different suppliers will, therefore, need to be documented by the topical product developer. The excipient vendor will be asked for both test results and test methods to establish that their excipient is qualitatively (Q1) the same as the excipient supplied by a competitor. This verification is easier for compendia excipients, but some of the National Formulary (NF) and United States Pharmacopeia (USP) monographs are sufficiently outdated such that even raw materials passing all the tests are not assured to be equivalent. For ANDA products, reverse engineering is used to select excipients that are the same as the excipients used in the reference listed drug (RLD).

	For innovator companies developing topical products, understanding the FDA concepts of Q1/Q2/Q3 is useful when they want to qualify a second source or when it becomes necessary to change from one excipient supplier to another during development. In both of these cases, the finished product produced before the excipient change needs to be shown equivalent to the finished product produced after the excipient change. For NDA submissions, the “test” product is the product manufactured later in development (i.e., second supplier or replacement vendor), and the “reference product” is the earlier product manufactured in development. For generics, the “test” product is the generic formulation and the “reference” product is the RLD. As stated by Chang et al. (2), “For semi-solid preparations, Q1/Q2 is not a must for generic products to be acceptable by the agency. However, the generic firm will face more regulatory scrutiny for a non-Q1/Q2 formula and need to demonstrate that the physicochemical characteristics, critical quality attributes, and in-vitro flux rate of its drug products are in line with the RLD, especially considering the insensitivity of clinical endpoint bioequivalence studies.” 

	In broadest terms, the excipients responsible for preventing phase separation and providing microstructure to the product are the structure-forming excipients described in FDA’s scale-up and post-approval changes guidance for semisolids (SUPAC-SS) (5). For emulsions (creams and lotions), the emulsifiers provide this function. For gels, the gelling agent, such as carbomer or cellulose, will be the structure-forming excipient. Some products, such as ointments, will primarily contain an excipient that thickens upon cooling (e.g., petrolatum) to provide microstructure to the product. It is reasonable for the product developer to request samples of excipients that fall at the extremes of the raw-material specification range, especially for structure-forming excipients. For example, Carbopol 934 polymer (Lubrizol) has a specification range of 30,500 mPa-s to 39,400 mPa-s for a Lubrizol viscosity test (i.e., Brookfield viscosity for a 0.5% neutralized solution). Carbopol 934 polymer is known to be shear sensitive, so any design of experiment to characterize how mixing speed/mixing time influences finished product viscosity will require carbomer spanning the Carbopol 934 specification range for Brookfield viscosity. What may not be reasonable is to expect that the low-viscosity carbomer sample and the high-viscosity carbomer sample will be sourced from commercial-scale batches of Carbopol 934 polymer. Often times, it will be years between commercial batches falling near either extreme of the specification range. It is also unreasonable to expect a vendor to purposefully alter their commercial process from historically optimal settings to generate “tons” of material in an attempt to satisfy one company’s need for a few kilograms of unexpired raw material at the edge of a specification range. It should be expected by excipient vendors, product developers, and FDA that samples of raw materials manufactured at the edges of the vendor’s specification range will be laboratory-scale material.

API crystallization (precipitation) and suspended API particle changes.

 It is the product development scientist’s responsibility to assure that their topical product is not formulated on a solubility boundary that will cause the API to crystallize due to minor changes in temperature, normal lot-to-lot variability in excipients, or end of shelf-life evaporation (weight loss) of a volatile solvent such as alcohol. It is also the product development scientist’s responsibility to identify potential excipient impurities, such as multivalent ions, that might react with the API and trigger precipitation.

	It is the excipient vendor’s responsibility to identify highly reactive species, such as residual catalyst, that might occur at trace levels in the excipient. Because excipient vendors typically already test for heavy metals, according to 

 <232> (6), and residual solvents, according to 

 <467> (7), it is unlikely that embracing QbD will require significant additional effort from excipient vendors to assure that the raw material they provide does not precipitate the API or cause a change in API form during storage.

 For many years, topical product formulators would write in batch records “mix until dissolved” and leave an area for “start time,” “finish time,” and “mix speed” to be entered. This practice was common as related to dissolving methyl paraben into the water phase or propyl paraben into the oil phase. In recent years, regulatory investigators have required that a specific mixing speed and duration be specified in the batch record. Formulators know that for some solute/solvent combination of excipients, the time required for complete dissolution can vary by hours. It is expected that the excipient vendor will know how best to add their raw material into a commercial-scale batch. Does heating help? Should the excipient be dissolved in a separate vessel and added as a concentrated solution? Does a wand or inductor need to be used to evenly distribute the excipient without clumping? This information is usually available in the technical package that describes the excipient. It is reasonable for an excipient vendor to be sufficiently aware of QbD terminology to use phrases such as “critical material attribute (CMA)” and “critical process parameter (CPP)” in their technical literature. An example would be describing a typical CPP for forming a smooth gel with the excipient supplier’s gelling agent.

Water is the excipient associated with the greatest risk of microbial contamination of a topical product. Fortunately, pharmaceutical water quality is well understood, and standardized testing assures that this risk is minimized in a compliant pharmaceutical product manufacturing facility. The inactive ingredients database (IID) lists ingredients (8) contained in approved topical products that cover the full range of risk for being the source of microbial contamination in the finished product. At one end of the spectrum are natural excipients, such as lecithin and tallow glycerides, that may be prone to microbial contamination. At the other end of the spectrum is isopropyl alcohol, which is a potent antiseptic that has no risk of microbial contamination during storage as a neat liquid.

	At least three of the significant product contamination situations in the author’s experience were similar because they occurred with: 1) high-volume products, 2) that had been successfully manufactured for over a decade without any indication that the product could be susceptible to microbial contamination, and 3) the source of contamination was unambiguously traced to an excipient that had recently experienced a change in process or source. In one of these situations, the raw material was a powder contaminated with Bacillus spores. The product was biocidal to the spores, but it took a few days for the formulated product to kill the spores. Thus, only product samples that were neutralized (prepared for microbial limit testing) within hours of completing the batch revealed contamination. Resampling and retesting of the product a few days later never confirmed that the product was contaminated.

	It is reasonable for the excipient vendor to provide excipients that do not have significant lot-to-lot variability in the amount of microbial content. It is also reasonable that the excipient vendor knows (and clearly communicates to the product developer) the identity of all microbes that are known to be contained in the raw material. If the specific microbes contained in a raw material are dependent upon a specific manufacturing site or source of a starting material, the vendor is responsible to know their excipient well enough to set meaningful specifications and clearly communicate details to the product developer.

 If the API can be ionized, then pH of the finished product will be a critical quality attribute and the pH of the bulk should be adjusted to a target value. In this scenario, lot-to-lot variability in the acid-base properties of an individual excipient is unlikely to significantly influence the ability to reach the target pH value. If the pH of an excipient trends up or down with storage, then that could be vital information for the product development scientist. A raw material re-assay date of less than a year may be required. For products that do not have a pH adjustment step during processing, such as ointments or other non-aqueous topical products, the acid-base properties of each individual excipient may become important. It is the responsibility of the formulator to determine the influence of different excipients on finished product pH. However, it is the responsibility of the excipient vendor to communicate (e.g., through technical product brochures) raw material pH variability for different lots at the time of release and how (and why) raw material pH changes upon storage.

 It has been shown that by reducing moisture, residual catalyst, peroxide levels, and aldehyde levels from excipients commonly used in topical products (e.g., PEG 400, Polysorbate 80, Dimethyl Isosorbide), significant improvements in API chemical stability and/or physical stability of topical product can be obtained (9). Although it is the formulator’s responsibility to determine compatibility between excipients and the API, it is the responsibility of the excipient supplier to produce a consistent raw material that clearly states the levels of reactive impurities in their raw material. The excipient vendor should know if (and to what extent) these impurities are likely to change over time and have a shelf-life or re-assay date for the raw materials that they supply. Reactive impurities should have an actual value reported in the certificate of analysis (COA) even though the specification is “less than” a limit value. Few things are worse than a formulator developing a product with multiple lots of surprisingly good raw material, only to be faced with a recall during the first year of commercial production due to out-of-specification stability results. A hypothetical example would be a residual catalyst that happened to vary between 0.1 and 0.3 ppm for the three lot numbers that were used during development. The specification for residual catalyst on the COA is less than 50 ppm with the specific result being listed as “meets test.” The formulator has no way of knowing that this value typically ranges between 0.5 ppm and 5 ppm with the occasional spike up to 30 ppm unless the vendor provides the numerical test result for each lot of excipient. For product development companies that embrace QbD, the excipient supplier must be as transparent as possible concerning variability in their dermatology product excipients.s

	The goal of Part I of this two-part series was to familiarize the excipient supplier with some of the QbD concepts and terminology specifically related to topical pharmaceutical products. With this understanding of QbD, it should be possible to build more effective partnerships between topical product development scientists and topical excipient vendors. Part II of this series focused on an important aspect of this partnership-what are reasonable customer expectations regarding excipient information and sample requests? In general, the excipient vendor should thoroughly characterize the qualitative (Q1) aspects of their material, provide laboratory-scale samples of excipient at the edge of the vendor specifications, and closely monitor and report lot-to-lot variability of critical properties/impurities of the excipient.

	The pharmaceutical industry is embracing QbD for topical products for both NDA and ANDA products. QbD is truly the new paradigm in topical pharmaceutical product quality for the 21st century both for products currently in development and for products that have been on the market for many years. Excipients and excipient vendors are of vital importance to QbD and, therefore, need both an understanding of QbD principles and consensus regarding reasonable expectations for excipient information and sample requests.

Guidance for Industry Nonsterile Semisolid Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation 

 Chapter <232>, “Elemental Impurities-Limits,” (US Pharmacopeial Convention, Rockville, MD, 2013).	

 Chapter <467>, “Residual Solvents” USP37 (US Pharmacopeial Convention, Rockville, MD, 2011).	

		FDA, “Inactive Ingredient Search for Approved Drug Products,” 

www.accessdata.fda.gov/scripts/cder/iig/index.Cfm

		N.A. Langley and K.H. Chen, “Case Study: Polyethylene Glycol Purity,” 

www.pharmaceuticalonline.com/doc/polyethylene-glycol-purity-0001

	David W. Osborne is chief scientific officer and founder of 

, 4215 Creekside Court, Fort Collins, CO 80525, 

	When referring to this article, please cite it as D. Osborne, "Impact of Quality by Design on Topical Product Excipient Suppliers, Part II: Reasonable Expectations," 

This article will clarify reasonable expectations for the responsibilities of topical product formulation developers and for excipient suppliers regarding the information and samples for experiments needed for QbD.

Impact of Quality by Design on Topical Product Excipient Suppliers, Part II: Reasonable Expectations

	Peer-Reviewed: 
	Submitted: Jan. 8, 2016. Accepted: Jan. 28, 2016.  

Quality by design (QbD) is a scientific and risk-based approach to product development that begins at the product concept stage. This article will equip the excipient vendor with an understanding of QbD from the perspective of the topical pharmaceutical product manufacturer.

	The US Food and Drug Administration (FDA) began an initiative in 2002 entitled 

Pharmaceutical Current Good Manufacturing Practices for the 21

, which encouraged the pharmaceutical industry to adopt modern quality management techniques (1). As a participant in the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals of Human Use (ICH), FDA contributed to a number of guidelines such as 

Q10 (5). These modern quality management techniques framed in terms of pharmaceutical regulatory concepts have been collectively called quality by design (QbD). QbD can be defined as a scientific, risk-based, holistic, and proactive approach to pharmaceutical product development. It begins at the product concept stage and is applied throughout development and into commercialization.

	The QbD paradigm performs a risk assessment during the product concept stage to identify active and excipient attributes having a high likelihood to affect critical quality attributes (CQAs) of the pharmaceutical product. Experimentation is then performed to determine impact of formulation (active and excipient) attributes and processing parameters on pharmaceutical product attributes, and a control strategy is adopted to mitigate risk of CQA failure. By understanding variation of excipient properties as they relate to critical process parameters (CPPs) and CQAs, the pharmaceutical product manufacturer can build robustness and flexibility into their manufacturing processes. Excipients and excipient vendors are of vital importance to QbD, and pharmaceutical product manufacturers are highly motivated to adopt the QbD paradigm. QbD is here to stay and will be embraced by the developers of new drug applications (NDAs) and abbreviated NDAs (ANDAs) for topical products.

	From the perspective of a pharmaceutical topical product development scientist, understanding and adopting QbD can be time consuming. It is hard to break the decades-old habit of limiting variability of the excipients so that an “optimized” product conforms to the narrowest specifications possible. The adoption of QbD for topical products prior to 2013 was further hindered by guidance documents often limiting their examples to oral solid-dosage forms. Fortunately for topical product developers, two papers have been published on the topic of generic development of topical dermatologic products (6, 7). These publications have made dramatic progress in clearing up misunderstandings about QbD as related to topical products. A third publication (8) describing the performance matrix for a topical cream provides a useful perspective on topical products being qualitatively equivalent (Q1), quantitatively equivalent (Q2), and structurally/functionally similar (Q3). Because QbD is a holistic approach that begins at the product concept stage and never really ends, product development scientists, process engineers, and technical support personnel require a broad understanding of QbD. While familiarity with the full spectrum of QbD is always useful, the excipient supplier can initially focus on QbD concepts specific to pharmaceutical excipients.

	The goal of Part I of this two-part series is to equip the excipient vendor with an understanding of QbD from the perspective of the topical pharmaceutical product manufacturer. The topical product scientist will apply these modern quality management techniques not only to products in development, but also to products that have been on the market for years. For excipient vendors to meet the needs of their pharmaceutical customers, it is important that they understand the broader QbD framework used by development scientists. This article will focus on aspects of QbD that are specific to excipients in topical dermatological preparations (both NDA and ANDA) that are meant to be locally active. Part II will discuss what specific information the excipient supplier should provide the development scientist to satisfy a QbD approach for topical product development.

	Risk criticality and the quality target product profile

	The starting point for QbD is the quality target product profile (QTPP). The QTPP is a prospective summary of the quality characteristics of a drug product that will ideally be achieved to ensure the desired quality, taking into account the safety and efficacy of the drug product (9). According to 

	“Could include the intended use in a clinical setting, route of administration, dosage form, delivery systems, dosage strength(s), container-closure system, therapeutic moiety release or delivery and attributes affecting pharmacokinetic characteristics (e.g., dissolution, aerodynamic performance) appropriate to the drug product dosage form being developed, and drug product quality criteria (e.g., sterility, purity, stability, and drug release) appropriate for the intended marketed product.”

	The QTPP is different from the product specification because the QTPP should include patient-relevant, product-performance elements such as clinical efficacy/bioequivalence or stability that are not carried out in batch-to-batch release. It provides an understanding of what will ensure the quality, safety, and efficacy of a specific product for the patient and is the starting point for identifying the CQAs, CPPs, and control strategy. The introduction of ICH Q9 (11) states that: “…the protection of the patient by managing the risk to quality should be considered of prime importance.” The ICH 

Quality Implementation Working Group Points to Consider

 (12) states: “Risk includes severity of harm, probability of occurrence, and detectability, and therefore the level of risk can change as a result of risk management. Quality attribute criticality is primarily based upon severity of harm and does not change as a result of risk management. Process

parameter criticality is linked to the parameter’s effect on any critical quality attribute. It is based on the probability of occurrence and detectability and therefore can change as a result of risk management.”

	CQAs are product attributes that have the potential to be altered by changes to process parameters or formulation variables during pharmaceutical development. If a product attribute cannot change during the pharmaceutical development process, even though it is an essential element of a marketable product, then that product attribute should not be a CQA. In addition to having the potential to change during development, a CQA must also be directly related to the safety and efficacy of the topical product. Selection of appropriate, product-performance-focused CQAs represents the biggest QbD challenge for topical liquid and semisolid products. A CQA is usually an attribute of the final product, but it is also possible to indicate a CQA of a raw material.

	Although it is possible for a raw material to be a CQA, it is much more likely that an excipient will be a critical material attribute (CMA). It is well recognized that excipients can be a major source of variability in topical products. CMAs such as pH, particle size distribution, particle aggregation, or appearance of a single excipient may dominate the analogous CQA of the final pharmaceutical product. Lionberger 

 states “Independent critical material attributes (CMAs) are the best way to provide a mechanistic link of the product quality to the critical process parameters in the manufacturing process” (13). This means that independent CMAs may better define product quality than CQAs. For example, 

 release testing (IVRT) using a Franz cell for a topical gel product containing suspended drug might seem like the best way to evaluate the manufacturing process. Thus, IVRT is designated as a CQA and is used to evaluate the impact of different mix times and mix speeds used to form the gel and suspend the drug. IVRT results are gathered for 6–10 gels to characterize mixing during manufacturing. This approach is a reasonable way to establish a design space for this product, but is it the best way? The quote from Lionberger 

 suggests that the product development scientist should consider defining API particle size and gel rheology as independent CMAs rather than defining 

 release as a CQA. A potential scenario in which these two CMAs would provide a mechanistic link is when the higher mix speed generates heat that alters particle size. At the same time, higher mix speeds reduce the gel viscosity by lowering the molecular weight of the shear-sensitive gelling agent. The IVRT response surface may be less sensitive to potentially “competing” changes in particle size and viscosity compared to the particle size response surface and viscosity response surface generated from the same 6–10 gel experimental design.

	QbD concerns of topical product development scientists

	When focusing on topical product risk and criticality as related to raw materials, typical CQA items are phase separation, rheology, precipitation of dissolved active/excipient or particle changes in suspended active, microbial contamination, pH, assay/impurities, heavy metals, and residual solvents.

. Phase separation of a topical product in a multi-use container can result in super-potent dosing for some of the treatment applications and sub-potent dosing for the remaining treatment applications. In the example QTPP for fluorouracil cream (7), this element was labeled “homogeneity and tube uniformity.” Phase separation can be most dramatic when the active is found primarily in the dispersed phase of a product that contains little of the dispersed phase (e.g., a hydrophobic drug that is almost completely dissolved in the oil phase of an oil-in-water emulsion that has more than 85% water). If this product is a cream that separates into a half milliliter of oil-rich phase that is at the orifice of the tube, then 90% of the drug may be applied in the first few applications. Alternatively, if the separated oil-rich phase of a lotion creams to the top of a bottle fitted with a pump that has a long dip tube, then 90% of the drug may remain inside the bottle and never be applied. Another example is when a gel containing uniformly dispersed solid-drug particles loses viscosity on storage and the previously dispersed drug falls to the bottom of the container. For topical products that are semisolids or fluid dispersions, assuring content uniformity (i.e., avoiding phase separation) tends to dominate the control strategy.

Rheology is the science that characterizes the flow of materials. For topical products, rheology considers the impact of shear on the apparent viscosity of a non-Newtonian liquid. Rheological behavior is directly correlated to microstructure of a topical product formulation. For two products that have the same composition (qualitatively [Q1] and quantitatively [Q2] the same), if they have the same microstructure (Q3), then these two products will have the same bioavailability. The manufacturing process can have a significant impact on the formulation microstructure (6). This means that characterizing rheological behavior as a function of excipient variability, processing parameters, and even active purity or particle size distribution may provide valuable insight with regards to the microstructure of the product. Dramatic change in rheological properties may affect the bioavailability. This impact applies to rheological changes over the shelf-life of the product, lot-to-lot changes in the rheology of the product, and differences in rheological properties between a generic formulation and the reference listed drug.

 If the API is completely dissolved in the topical product, then it must remain completely dissolved over the shelf life of the product. Because only dissolved drug penetrates the stratum corneum of intact skin (14), the precipitation of drug is expected to change bioavailability. Formulations that are prone to supersaturation, followed by unpredictable timing for precipitation, are rarely viable commercial products. Likewise, topical products formulated near API saturation that precipitate with relatively small drops in temperature need to rapidly redissolve upon storage at their labeled temperature range to be viable commercial products. Concerns about precipitation midway through stability of a material completely dissolved at product release are not limited to API. A good illustration of the preservative methylparaben precipitating out of a topical gel is provided in the specification and examples of US patent 8,053,427 (15).

If the drug substance is dispersed in the formulation as solid particles, particle size and content uniformity throughout the entire container/closure system will be two critical attributes for the topical drug product. Characterization of segregation and/or aggregation of particles will be necessary, in addition to demonstrating that no changes in the drug substance polymorph occur throughout the stability studies. Particle size of the drug substance throughout the shelf life of the topical product must be determined and may need to be controlled. For particles less than 10 microns, changes in particle size and/or morphology of suspended drugs in topical products are presumed to change bioavailability (14, 16).

It is important that products applied to the skin are not contaminated by bacteria or fungi and for this reason, topical products, especially products packaged in multiple-use containers, are usually preserved. Healthy skin provides a reasonably effective barrier against microbes, but this barrier is often compromised in skin conditions that are treated with topical products. Products applied to the face will eventually find their way into a patient’s eyes, which is another reason that even vehicle controls must be adequately preserved to assure patient safety. For topical products, passing 

 <51> Antimicrobial Effectiveness Testing (AET) over the entire product shelf life is sufficient to assure that if contaminated, the product will not support growth and be a risk to the patient (17). AET testing assumes that incoming raw materials will not have significant lot-to-lot differences in the level of bacteria/fungi contaminating the API or excipients that are used to make the product.

 Most topical formulations will be adjusted to a specified pH at some point during processing. If the pH remains stable over the shelf-life of the product, then an appropriate control strategy can be put into place to keep pH as a very low risk, non-critical quality attribute. However, some actives degrade into weak acids (e.g., benzoyl peroxide degrading into benzoic acid) and if the product is not buffered (or insufficiently buffered), then the pH steadily drops over the shelf life of the product. If the active has pH-dependent solubility or a dissociation constant near the product pH, then it is likely that bioavailability may change with changing pH (8). The acid/base properties of some excipients can significantly impact the initial pH of the formulation. Lot-to-lot variability of excipients that can shift pH should be a risk mitigation focus for APIs that carry charge.

Assay tests that are specific, accurate, and precise are mandatory to quantify the amount of API present (per unit weight or volume) in the topical drug product. Likewise, impurity tests are required for specified impurities as justified by ICH Q3B (18) qualification threshold and unspecified impurities as justified by the identification threshold based on the maximum daily dose for the drug product (7). Excipients must be compatible with the API, and drug–excipient incompatibility is usually noted early in development and the formulation modified to assure an adequate shelf-life. A much more difficult problem is when trace level substances (e.g., catalysts, heavy metals, unreacted reagents) contained within an excipient are incompatible with the API. Degradation of the API may be rapid and limited by complete consumption of the trace levels of the excipient impurity. Usually this degradation of the activewill be viewed as a processing loss and be ignored (if less than 1%) or corrected by use of an overage. However, if this reactive trace excipient impurity has significant lot-to-lot variability or is not uniform throughout the excipient batch, then the drug product may risk occasional lots failing on stability.

 The drug product manufacturer will always be concerned about complying with 

 General Chapter <467> Residual Solvents (19) and 

 General Chapter <232> Elemental Impurities-Limits (20). The requirements include not exceeding limits for the finished drug product by controlling the elemental impurities and residual solvent of excipients. It should be noted that topical products may contain a significant amount of solvent (e.g., ethyl alcohol) and for these products, the solvent used is counted as an excipient, not a residual solvent (6).

	The goal of Part I of this series is to familiarize the excipient supplier with some of the QbD concepts and terminology specifically related to topical pharmaceutical products. The pharmaceutical industry is embracing QbD for topical products for both NDA and ANDA products. With this understanding of QbD, it should be possible to build more effective partnerships between topical product development scientists and topical excipient vendors. QbD is truly the new paradigm in topical product development and is providing patients with more robust treatment options. Part II will propose reasonable customer expectations regarding excipient sample requests and specific information about excipients needed for the QbD approach.

ICH Harmonised Tripartite Guideline: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions

, Step 4. (Geneva, Switzerland, Nov. 1, 2007)	

ICH Harmonised Tripartite Guideline: Pharmaceutical Development

 (Geneva, Switzerland, August 2009).  	

ICH Harmonised Tripartite Guideline: Quality Risk Management

(Geneva, Switzerland, Nov. 9, 2005).  	

ICH Harmonised Tripartite Guideline: Pharmaceutical Quality System

 (Geneva, Switzerland, June 4, 2008). 	

 Q9 Quality Risk Management. (Silver Spring, MD, June 2006).	

Quality Implementation Working Group Points to Consider (R2) ICH-Endorsed Guide for ICH Q8/Q9/Q10 Implementation.

The Relationship Between Structure and Barrier Function of Skin. Chapter 1 Dermal Absorption and Toxicity Assessment, 

M.S. Roberts and K.A. Walters, Eds. (Marcel Dekker, New York, 1998) pages 1-42.	

		J.C. Buge, K. Nadau-Fourcade, and C. Meunier. "Bromonidine gel composition," US Patent 8,053,427, Nov. 8, 2011.	

 Chapter  <51>, "Antimicrobial Effectiveness Testing," 

 (US Pharmacopeial Convention, Rockville, MD, 2005), p. 2499. 	

ICH Harmonised Tripartite Guideline: Impurities in New Drug Products 

Q3B(R2) (Geneva, Switzerland, June 2, 2006).	

 (US Pharmacopeial Convention, Rockville, MD, 2011), 

 Chapter <232>, "Elemental Impurities-Limits," (US Pharmacopeial Convention, Rockville, MD, Feb. 1, 2013), 

	David W. Osborne is chief scientific officer and founder of Independent Derm Solutions, LLC, 4215 Creekside Court, Fort Collins, CO 80525, dosborne@independentdermsolutions.com. 

	When referring to this article, please cite it as D. Osborne, "Impact of Quality by Design on Topical Product Excipient Suppliers, Part I: A Drug Manufacturer's Perspective," 

This article will equip the excipient vendor with an understanding of QbD from the perspective of the topical pharmaceutical product manufacturer.