Silver Sprnig M, D 20993 -0002 Phone: 855-543-3784 or 301 -796-3400; Fax: 301 -431-6353
Microbiological Quality Considerations in Non-sterile Drug Manufacturing Guidance for Industry DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to https://www.regulations.gov. Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document, contact (CDER) Susan Zuk, 240-402-9133. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) September 2021 Pharmaceutical Quality/Microbiology Pharmaceutical Quality/Manufacturing Standards (CGMP) Microbiological Quality Considerations in Non-sterile Drug Manufacturing Guidance for Industry Additional copies are availablefrom: Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10001 New HampshireAve., Hillandale Bldg., 4th Floor Silver Spring, MD 20993-0002 Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 Email: druginfo@fda.hhs.gov https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) September 2021 Pharmaceutical Quality/Microbiology Pharmaceutical Quality/Manufacturing Standards (CGMP) Contains Nonbinding Recommendations Draft -- Not for Implementation TABLE OF CONTENTS I. INTRODUCTION...................................................................................................... 1 II. BACKGROUND ........................................................................................................ 2 III. STATUTORY AND REGULATORY FRAMEWORK............................................. 3 IV. MICROORGANISMS AND LIFECYCLE PRODUCT QUALITY.......................... 5 A. General Microbiological Concerns Regarding NSDs..................................................... 5 B. Risk-Based Impact Assessment ...................................................................................... 7 1. Product Specific Elements................................................................................................ 8 2. Manufacturing Elements.................................................................................................. 9 C. Microbiological Concerns for Specific Dosage Forms and Special Cases...........................12 1. Solid Dosage Forms.......................................................................................................12 2. Non-Solid Dosage Forms................................................................................................13 3. Microbiological Consideration Special Cases .................................................................14 D. Updating Approved Drug Product Specifications ...........................................................17 APPENDIX: CASE STUDY EXAMPLES OF MICROBIOLOGICAL CONTAMINATION OF NSD PRODUCTS; IMPACT ON PRODUCT QUALITY AND MANUFACTURING PROCESS......................................................................................... 21 Contains Nonbinding Recommendations Draft -- Not for Implementation 1 Microbiological Quality Considerations in 2 Non-sterile Drug Manufacturing 3 Guidance for Industry1 4 5 6 This draft guidance, when finalized, will represent the current thinking of the Food and Drug 7 Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 8 binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 9 applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 10 for this guidance as listed on the title page. 11 12 13 14 I. INTRODUCTION 15 16 This guidance is intended to assist manufacturers in assuring the control of microbiological2 17 quality of their non-sterile drugs (NSDs).3 The recommendations herein apply to solid non18 sterile dosage forms, as well as semi-solid, and liquid non-sterile dosage forms (e.g., topically 19 applied creams, lotions and swabs, and oral solutions and suspensions). NSDs can be 20 prescription or nonprescription drugs, including those marketed under approved new drug 21 applications (NDAs) or abbreviated new drug applications (ANDAs), and nonprescription drugs 22 without approved new drug applications which are governed by the provisions of section 505G 23 of the FD&C Act (often referred to as over-the-counter (OTC) monograph drugs).4 These 24 recommendations, if followed, will also assist manufacturers in complying with the current good 25 manufacturing practice (CGMP) requirements for finished pharmaceuticals and active 26 pharmaceutical ingredients (APIs).5 27 28 This guidance discusses product development considerations, risk assessments, and certain 29 CGMPs that are particularly relevant to microbiological control in a manufacturing operation for 30 a NSD. It also provides recommendations to help manufacturers assess the risk of contamination 31 of their NSDs with objectionable microorganisms in order to establish appropriate specifications 32 and manufacturing controls that prevent such contaminations and assure the safety, quality, 33 identity, purity, and efficacy of the NSD. 6 34 1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and Research (CDER) at theFood and Drug Administration. 2 For the purposes of this guidance, the terms "microbiological" and "microbial" are used interchangeably. 3 For the purposes of this guidance, non-sterile drugs (NSDs) refers to non-sterile finished dosage forms. 4 The term `OTC monograph drug' means a nonprescription drug without an approved new drug application which is governed by the provisions of section 505G. See FD&C Act section 744L(5). 5 See 21 CFR parts 210 and 211, CGMP for Finished Pharmaceuticals, and FD&C Act section 501(a)(2)(B) for APIs. 6 The term "objectionable microorganisms" as used here refers to organisms that are objectionable due to their detrimental effect on products or potential harm to patients or objectionable due to the total number of organisms. See 43 FR 45053 (Sep. 29, 1978). 1 Contains Nonbinding Recommendations Draft -- Not for Implementation 35 For application products (i.e., NDAs, ANDAs) this guidance also explains how applicants should 36 submit NSD controls in original submissions and report changes in microbiological 37 specifications and testing programs to the FDA, in accordance with current Agency guidances 38 regarding changes to an approved application. 39 40 To illustrate the importance of a microbiological risk assessment and control strategy, this 41 guidance discusses incidents of Burkholderia cepacia complex (BCC) and other microorganism 42 contamination in non-sterile dosage forms that resulted in adverse events and recalls of the drug 43 products. The guidance describes proper prevention of and testing for BCC in aqueous dosage 44 forms of NSDs. 45 46 The guidance describes the Agency's current thinking on microbiological contamination of 47 topical antiseptic drugs intended for use by health care professionals in a hospital setting or other 48 health care situations outside the hospital,7 which are used prior to medical procedures to reduce 49 the number of bacteria on the skin and that in some cases are not manufactured as sterile 50 products. 51 52 The contents of this document do not have the force and effect of law and are not meant to bind 53 the public in any way, unless specifically incorporated into a contract. This document is 54 intended only to provide clarity to the public regarding existing requirements under the law. 55 FDA's guidance documents should be viewed only as recommendations, unless specific 56 regulatory or statutory requirements are cited. The use of the word should in Agency guidances 57 means that something is suggested or recommended, but not required. 58 59 II. BACKGROUND 60 61 This guidance was developed, in part, as a result of the Agency's review of FDA Adverse Event 62 Reports (FAERs)8 and recalls involving contamination of non-sterile dosage forms. A review of 63 FAERs that occurred between 2014 and 2017 revealed 197 FAERs associated with intrinsic 9 64 microbiological or fungal contamination, and of those, 32 reported serious adverse events. 65 Because spontaneous reports10 in FAERs are voluntary by definition, the Agency anticipates a 66 degree of underreporting. The actual number of incidents associated with microbiological 67 contamination is likely significantly higher than the number of events reported.11 7 Such products includehealth care personnel hand washes, health care personnel hand rubs, surgical hand scrubs, surgical hand rubs, and patient antiseptic skin preparations (i.e., patient preoperative and preinjection skin prepa rations). 8 FDA Adverse Event Reporting System (FAERS) Latest Quarterly Data Files https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveilla nce/AdverseDrugEff ects/ucm082 193.htm. 9 Intrinsic means the microbial or fungal contamination originated with the manufacture, packaging, shipping, or storage of the drug, not from extrinsic sources, (e.g., consumer or health care provider use errors). 10 For definition of spontaneous report see FDA's The Public's Stake In Adverse Event Reporting https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveilla nce/AdverseDrugEff ects/ucm179 586.htm. 11 According to FDA's Question and Answers on FAERs, "FDA does not receive reports for every adverse event or medication error that occurs with a product...There are also duplicatereports where the same report was submitted by the consumer and by the sponsor [drug manufacturer]." https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveilla nce/AdverseDrugEff ects/. 2 Contains Nonbinding Recommendations Draft -- Not for Implementation 68 69 The review of voluntary recall actions during the same time period revealed over 50 events 70 associated with objectionable microbiologically contaminated NSDs.12 The recalls showed that a 71 wide range of objectionable microorganisms were found in both aqueous and non-aqueous 72 NSDs.13 73 74 The Agency is also aware of specific concerns regarding BCC and its association with 75 contamination of aqueous-based NSDs that resulted in a number of serious adverse events, i.e., 76 infections and deaths.14 In May 2017, FDA released a statement15 alerting drug manufacturers of 77 the recent product recalls associated with the presence of BCC in NSDs. The statement also 78 reminded drug manufacturers of their responsibilities to prevent objectionable microorganisms 79 from adversely impacting their NSD manufacturing processes, as well as the products 80 themselves. 81 82 Analysis of these events, combined with FDA's experience conducting microbiology 83 assessments of non-sterile drugs for NDA and ANDA products and compliance actions,helped 84 to inform the recommendations in this guidance.16 85 86 III. STATUTORY AND REGULATORY FRAMEWORK 87 88 Under section 501(a)(2) of the Federal Food, Drug, and Cosmetic Act (FD&C Act),17 a drug will 89 be deemed adulterated if: 90 91 "the methods used in, or the facilities or controls used for, its manufacture, processing, 92 packing, or holding do not conform to or are not operated or administered in conformity 93 with current good manufacturing practice to assure that such drug meets the requirements 94 of this Act as to safety and has the identity and strength, and meets the quality and purity 95 characteristics, which it purports or is represented to possess," or "if it has been prepared, 96 packed, or held under insanitary conditions whereby it may have been contaminated with 97 filth, or whereby it may have been rendered injurious to health." 98 99 For finished pharmaceuticals, the CGMP regulations described in 21 CFR parts 210 and 211 100 address prevention of objectionable microorganisms in non-sterile drug products, bioburden 101 specifications, and in-process testing. Specifically: 102 12 See footnote 6. 13 FDA Recalls, Market Withdrawals, & Safety Alerts - https://www.fda.gov/Safety/Recalls/default.htm. 14 Glowicz J et al, 2018, A multistate investigation of health careassociated Burkholderia cepacia complex infections related to liquid docusate sodium contamination, January-October 2016, Am J Infection Control, Vol 46: 649-665, https://www.ajicjournal.org/article/S0196-6553(17)31287-7/fulltext. 15 FDA advises drug manufacturers that Burkholderia cepacia complex poses a contamination risk in non-sterile, water-based drug products, May 2017, https://www.fda.gov/Drugs/DrugSafety/ucm559508.htm. 16 CDER began chemistry, manufacturing and controls (CMC) microbiology reviews of NSD in the mid-1990s with a focus on aqueous based NSDs. 17 See 21 U.S.C. 351(a)(2). 3 Contains Nonbinding Recommendations Draft -- Not for Implementation 103 21 CFR 211.113(a), Control of microbiological contamination, states that appropriate 104 written procedures, designed to prevent objectionable microorganisms in drug products 105 not required to be sterile, shall be established and followed. 106 107 21 CFR 211.110(a)(6), (b), (c), Sampling and testing of in-process materials and drug 108 product, requires (where appropriate) in-process bioburden testing and valid in-process 109 specifications to assure the drug product meets its microbiological specifications. In- 110 process testing shall occur during the product process, e.g., at commencement or 111 completion of significant phases or after storage for long periods. 112 113 21 CFR 211.84(d)(4) and (6), When appropriate, components shall be microscopically 114 examined. Each lot of a component, drug product container, or closure with potential for 115 microbiological contamination that is objectionable in view of its intended use shall be 116 subjected to microbiological tests before use. 117 118 To assure the microbiological quality of NSDs subject to premarket approval, applicants must 119 propose appropriate drug substance and product specifications (i.e., tests, analytical procedures, 120 and acceptance criteria) in their submissions in accordance with 21 CFR 314.50(d)(1) [NDAs] 121 and 21 CFR 314.94(a)(9) [ANDAs].18 122 123 In general, a drug with a name recognized in an official compendium must comply with the 124 United States Pharmacopeia (USP) compendial standards for identity, strength, quality, and 125 purity, or be deemed adulterated, misbranded, or both.19 If USP has established a monograph for 126 a drug, the USP monograph will identify the official tests, procedures, acceptance criteria, and 127 other requirements. When USP monographs include a test or specification referencing 128 "Applicable General Chapters,"20 the applicant should ensure that their monograph product 129 complies with the testing requirement, or it could be deemed adulterated. Some of the USP 130 General Chapters that are more commonly referenced in drug monographs, as they apply to 131 controlling microbiological activity in NSDs, include, for example: 132 133 · USP <60> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS 134 TESTS FOR BURKHOLDERIA CEPACIA COMPLEX 135 · USP <61> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS: 136 Microbial Enumeration Tests 137 · USP <62> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS: 138 Tests for Specified Microorganisms 139 18 For the definition of specification, see 21 CFR 314.3(b) and also ICH guidance for industry Q6A Specifications: Test Procedures and AcceptanceCriteria for New Drug Substances and New Drug Products: Chemical Substances (December 2000). 19 FD&C Act 501(b) and 502(e)(3)(B) and (g); also 21 CFR 299.5. 20 See USP, Conformance to Standards, 3.10, "Applicable general chapters" means general chapters numbered below 1000 or above2000 that are made applicable to an article through reference in General Notices, a monograph, or another applicable general chapter numbered below 1000." 4 Contains Nonbinding Recommendations Draft -- Not for Implementation 140 In addition to USP monograph requirements, further microbiological tests are often performed as 141 part of batch release requirements as described in 21 CFR part 211.21 142 143 Objectionable microorganisms and bioburden in non-sterile APIs should be controlled. FDA 144 guidance for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical 145 Ingredients (September 2016) states: 146 147 "Appropriate specifications should be established for APIs in accordance with accepted 148 standards and consistent with the manufacturing process. The specifications should 149 include control of impurities (e.g., organic impurities, inorganic impurities, and residual 150 solvents). If the API has a specification for microbiological purity, appropriate action 151 limits for total microbial counts and objectionable microorganisms should be established 152 and met." 153 154 IV. MICROORGANISMS AND LIFECYCLE PRODUCT QUALITY 155 156 A. General Microbiological Concerns Regarding NSDs 157 158 Prevention, control, and monitoring of the microbiological population in non-sterile drug 159 components and drug products are necessary to minimize the risk of: 160 161 · patient exposure to significant numbers or harmful species of microorganisms, especially 162 in immunocompromised patients22 163 · patient exposure to harmful microbial metabolites and/or toxins 164 · drug spoilage or degradation 165 166 The statutory and regulatory framework described in section III above, coupled with sound 167 scientific rationale, provides the foundation for establishing a program to monitor and control the 168 manufacturing process to prevent objectionable microorganisms from affecting the quality of a 169 NSD. 170 171 To ensure product quality and patient safety, it is essential to limit the level and type of 172 microorganisms in NSDs during manufacturing and over product shelf life. While a NSD is not 173 required to be sterile, there is a threshold of microbiological content above which safety and 174 efficacy of a given NSD may be adversely impacted. 175 176 The CGMP regulations require that components are sampled, tested, or examined prior to release 177 by the manufacturer's quality control unit.23 Naturally-derived components (e.g., plant or animal 178 derived ingredients, and naturally occurring ingredients such as water) may contribute 179 significantly to the total bioburden of the drug product and must be subjected to microbiological 21 CGMPs are not limited to drugs marketed under approved applications. See FD&C Act section 501(a) and 21 CFR parts 210 and 211. 22 For the purposes of this guidance, we define immunocompromised patients as those who have a weakened immune system, which may be dueto trauma, surgery, illness, or chronic disease. It also includes vulnerable populations, such as infants and the elderly. 23 See 21 CFR 211.84. 5 Contains Nonbinding Recommendations Draft -- Not for Implementation 180 testing in accordance with established procedures.24 For instance, water is a common component 181 used in NSD manufacturing. However, water system control deviations can be difficult to detect 182 due to limitations of sampling.25 These deviations may lead to the formation of biofilms and 183 have been shown to have a profound impact on microbial quality of an aqueous-based drug. 184 Consequently, proper water system design and control, appropriate microbial action limits,26 and 185 routine water quality testing is critical to assuring that microbial levels are below established 186 limits, and that the water is free of objectionable microorganisms.27 Therefore, it is important for 187 manufacturers to have a robust design for water systems, including controls designed to prevent 188 objectionable microorganisms and procedures for monitoring, cleaning, and maintenance.28 189 190 Aqueous non-sterile products, which may support microbial growth during the product shelf life 191 due to their water activity (aw),29 should be designed to prevent microbial proliferation of 192 intrinsic microorganisms or those inadvertently introduced during use. While the potential for 193 microbial growth during the manufacturing process or over storage through the shelf life can be 194 partially mitigated by a properly designed preservative system or formulation, antimicrobial 195 preservatives can provide a false sense of product safety regarding the presence or growth of 196 microorganisms. Two purposes of a preservative are to counteract possible incidental microbial 197 contamination during multiple uses of a product by a consumer and maintain microbial control 198 over the shelf life of the product. Preservatives are not a substitute for a comprehensive approach 199 to preventing objectionable microorganisms from contaminating NSDs, and should not be 200 presumed to reduce in-process bioburden during manufacturing. Certain microorganisms have 201 been found to degrade commonly used preservatives, despite the drug having previously met 202 antimicrobial effectiveness testing acceptance criteria. Consequently, non-sterile drug 203 manufacturers should be aware of the potential for the development of preservative resistance. 204 This potential decrease in preservative effectiveness should be investigated (root cause analysis 205 and corrective action to eliminate the source of contamination) in cases of objectionable 206 microbes or an upward trend in total microbial enumeration counts. This issue is discussed as a 207 special case study regarding Burkholderia cepacia complex and Aqueous Drug Products in 208 section IV.C.3.a Microbial Considerations Special Cases of this guidance. 209 210 In contrast, many non-sterile liquid products that are not aqueous-based, such as those containing 211 high percentages of alcohol or other non-aqueous solvents, can potentially pose lower risk of 212 microbial proliferation during processing, holding of in-process materials, and storage over shelf 24 See 21 CFR 211.84(d) and 211.113(a). 25 An effectiveand ongoing monitoring program is important in determining if water used to support batch manufacture continues to meet predetermined quality characteristics. For products that includewater in manufacturing operations, more sensitive water sampling strategies are generally appropriate, and should include use of larger sample sizes (e.g., 100 mL) with membrane filtration. 26 Microbial action limits should be established based on therisk-based impact assessment, as described in section IV.B. 27 See 21 CFR 211.84(d). 28 See 21 CFR 211.63, 211.67, 211.100. 29 It is important to note that water activity is different from water content. USP <1112> defines water activity as the ratio of the vapor pressure of water in the drug, when in a completely undisturbed balance with the surrounding air media, to the vapor pressureof distilled water under identical conditions. See USP <1112> APPLICATION OF WATER ACTIVITY IN DETERMINATION TO NONSTERILE PHARMACEUTICAL PRODUCTS. In contrast, water content is the amount of moisture in the drug. 6 Contains Nonbinding Recommendations Draft -- Not for Implementation 213 life.30 Also, non-sterile solid drug products, such as tablets and capsules, have a low water 214 activity that usually does not allow for microbial growth during product shelf life. However, it 215 should be noted that although microorganisms that are present in a non-sterile drug product with 216 low water activity will not proliferate, they can persist in non-aqueous liquids and dry products 217 throughout the shelf life of the product. The CGMP regulations require that written procedures 218 be established to prevent introduction of objectionable microbiological contamination in the 219 manufacture of drug products not required to be sterile, and that a program be designed to assess 220 the stability characteristics of drug products, including NSD. 31 Consequently, it is important to 221 provide for appropriate microbiological control of the components (e.g., excipients and APIs) of 222 non-sterile drug products, even if the components possess a low water activity. 223 224 Non-sterile solid drug products also can be at risk for microbial proliferation through 225 contamination during manufacturing. For example, extended in-process hold times of aqueous 226 solutions or slurries at various points in the manufacturing process of a solid drug product could 227 allow for microbial proliferation exceeding the appropriate levels for such dosage forms. 228 Consequently, procedures that establish time limits are essential to assure product quality, 229 including control of microbiological quality, at each process step used in the manufacture of both 230 liquid and solid NSDs to prevent objectionable microorganisms.32 231 232 While not exhaustive, the USP provides a widely accepted set of microbiological test methods 233 for non-sterile drug products.33 USP also recommends the establishment of acceptance criteria 234 regarding total numbers of microorganisms, in addition to selected specified microorganisms in 235 NSDs.34 However, the USP does not provide a comprehensive list of objectionable 236 microorganisms; therefore, firms should identify any additional controls and acceptance criteria 237 that are necessary. The need for additional controls of objectionable microorganisms should be 238 determined for each product. For example, the presence of BCC in aqueous non-sterile drug 239 products may lead to both drug product degradation and patient infection. The intended patient 240 population, drug product indication, and route of administration should be considered when 241 establishing a microbial specification and determining if a specific microorganism is 242 objectionable in the drug product. 243 244 B. Risk-Based Impact Assessment 245 246 The controls necessary to prevent objectionable microorganisms will depend on the risk 247 (probability and hazard potential) of microbiological contamination in the NSD, including the 248 characteristics of the NSD (e.g., formulation, component selection, conditions of use, and route 249 of administration), the NSD manufacturing process, and the impact of the manufacturing 250 environment. Well-designed and appropriately controlled manufacturing processes present fewer 251 opportunities for introducing objectionable microorganisms and their proliferation or growth. For 252 certain low-risk manufacturing operations (e.g., tablet manufacture), reduction in 30 There have been recalls in alcohol based products. Refer to Appendix, Case 6. 31 See, e.g., 21 CFR 211.113 and 211.166(a). 32 See 21 CFR 211.111 and 211.113(a). 33 USP <61> MICROBIAL ENUMERATION TESTS and USP <62> TESTS FOR SPECIFIED ORGANISMS. 34 USP <1111> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS: ACCEPTANCE CRITERIA FOR PHARMACEUTICAL PREPARATIONS AND SUBSTANCES FOR PHARMACEUTICAL USE. 7 Contains Nonbinding Recommendations Draft -- Not for Implementation 253 microbiological monitoring and testing may be justified using a risk assessment (see section C 254 below). 255 256 A risk-based impact assessment helps manufacturers identify product-specific characteristics and 257 manufacturing process elements that are more likely to introduce bioburden or objectionable 258 microorganisms into the NSD. Systems designed to mitigate risks based on this risk-based 259 impact assessment are more likely to prevent objectionable microorganisms in NSDs. The 260 elements listed below, while not an exhaustive list, should be considered in the risk management 261 plan to reduce objectionable microorganisms, where relevant. 262 263 1. Product Specific Elements 264 265 o Dosage Form 266 Liquid products typically have a higher potential for microbial growth 267 than other types, and semi-solids typically have a higher potential for 268 microbial growth than solids.35 269 270 o Water Activity 36 271 Water activity of non-aqueous NSDs should be low enough to inhibit 272 microbial growth. 273 When NSDs have a higher water activity, there is higher potential for 274 microbial growth and additional manufacturing controls may be needed. 275 276 o Proposed Use 277 Consider the patient populationthe spectrum of patients that could be 278 exposed to the drug and disease state of the most vulnerable patients 279 taking the drug. 280 Consider the route of administration. 281 Consider the body site to which the NSD may be administered (e.g., the 282 skin, the respiratory tract, the gastrointestinal tract, or the urinary tract), 283 and whether the tissue may be injured or diseased, and therefore more 284 susceptible to infection. 285 Consider the setting in which the product is used (e.g., operating room, 286 NICU). 287 288 35 Dosage form will dictate the typeof and extent to which microbial enumeration testing should be performed on the finished product. General enumeration testing is described in USP <61> and USP <62>. For solid dosage forms, ICH Q6A Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances includes recommendations for conditions under which "periodic or skip testing" with regard to microbial enumeration testing may be considered. 36 USP <1112> APPLICATION OF WATER ACTIVITY DETERMINATION TO NONSTERILE PHARMACEUTICALPRODUCTS - Reduced water activity (aw) will greatly assist in the prevention of microbial proliferation in pharmaceutical products; the formulation, manufacturing steps, and testing of nonsterile dosage forms should reflect this parameter. 8 Contains Nonbinding Recommendations Draft -- Not for Implementation 289 o Packaging 290 Ensure container/closure provides adequate protection from foreseeable 291 external factors that can lead to microbial contamination (e.g., water or 292 microbial ingress).37 293 Consider the appropriateness of a single-dose versus a multiple-dose 294 container-closure when selecting the NSD packaging.38 For certain dosage 295 forms, a single-dose container/closure might provide superior safety with 296 respect to preventing extrinsic microbial ingress into the finished product. 297 298 o Product Components and Composition 299 Consider selection of appropriate preservatives that assure effectiveness to 300 prevent microbiological proliferation throughout the shelf life. 301 Assure all incoming lots of raw materials are suitable for their intended 302 use, including acceptable microbiological quality.39 303 304 o Microbiological TestingProduct Specific Considerations 305 Establish appropriate microbial limits for components, in-process 306 materials, and finished products.40 307 Ensure the sampling plan detects variation within a batch.41 308 Ensure appropriate sensitivity of methods for detecting a variety of 309 microbes that could be in components or the finished product and that 310 could pose a risk to patients or product stability.42 311 Implement appropriate action limits and test methods for water that is used 312 as a component, including use as a processing aid. 43 Purified water, USP, 313 that does not exceed 100 CFU/ml is recommended for use in solid oral 314 dosage forms. More stringent microbiological quality standards may be 315 appropriate for other dosage forms.44 316 317 2. Manufacturing Elements 318 319 o Manufacturing Process Steps: Certain processing steps may have a greater impact 320 than others in either promoting or reducing bioburden. 321 Bulk storage steps, especially those that are aqueous-based in the 322 manufacturing process, may create conditions in which microorganisms 323 can proliferate, particularly during extended in-process holding periods 324 (i.e., time between different unit operations). Other manufacturing steps 325 might introduce objectionable microorganisms. Therefore, extended 326 holding of aqueous in-process materials (e.g., coating 327 suspensions/solutions, liquid mixtures prior to the addition of a 37 CFR 211.94(b). 38 USP <659> PACKAGING AND STORAGE REQUIREMENTS. 39 See 21 CFR 211.84(d)(6). 40 See 21 CFR 211.113(a). 41 See 21 CFR 211.110(a). 42 See 21 CFR 211.160(b). 43 See 21 CFR 211.84(d)(6). 44 USP <1231> WATER FOR PHARMACEUTICAL PURPOSES. 9 Contains Nonbinding Recommendations Draft -- Not for Implementation 328 preservative) is not advisable. Holding time limits must be established to 329 preserve product quality.45 330 Inadequate equipment cleaning processes, such as extended hold times 331 before cleaning and insufficient drying after equipment has been cleaned, 332 may also promote microbiological contamination. 333 Inadequate environmental controls, such as production areas open to a 334 natural, uncontrolled, or insufficiently controlled environment when 335 product or product contact surfaces are exposed may promote 336 microbiological contamination. 337 Some manufacturing steps (e.g., those that involve filtration, high 338 temperature, extreme pH, or organic solvents) might result in an in- 339 process material that has a reduced bioburden. 340 341 o Components: Non-sterile components can be a source of objectionable 342 microorganisms in the manufacturing process. Appropriate specifications46 for 343 these components, as well as strategies for monitoring, controlling, preventing 344 objectionable microorganisms must be established.47 Special attention should be 345 given to purified water48 and naturally-derived components due to their intrinsic 346 risk for contamination. 347 348 o Water System: Water used as a component (or as a processing aid) must be, as for 349 any other component, of appropriate quality for its intended use in processing and 350 in the formulation. 49,50 When water used as a component is processed in-house, 351 the purification system must be well-designed and rigorously controlled and 352 maintained. 51 Maintenance and control of water purification systems should 353 include proactive replacement of parts to prevent deterioration and routine 354 monitoring to assure the system can consistently produce water meeting its 355 predetermined quality characteristics. The procedure for monitoring should 356 incorporate appropriate action and alert limits and include timely sampling after 357 key water processing steps and equipment used in the water processing and 358 delivery system, including all points-of-use. Water used as a cleaning agent, 359 depending on conditions of use and equipment, should be monitored to ensure it 360 meets appropriate quality for its intended use. 361 362 o Environment: Manufacturers must ensure that facilities, equipment, and 363 environmental conditions are adequate to ensure control of air quality for 364 manufacture, such as preventing introduction of microbiological contaminants or 365 bioburden that would be objectionable to the particular NSD being produced.52 45 See 21 CFR 211.111. 46 See 21 CFR 211.160(b). 47 See 21 CFR 211.100(a), 211.113(a). 48 USP <1231> WATER FOR PHARMACEUTICAL PURPOSES. 49 See 21 CFR 211.80, 211.84, 211.160(b). 50 USP <1231> WATER FOR PHARMACEUTICAL PURPOSES classifies different water quality grades to indicate relativepurity and absence of microorganisms. 51 See 21 CFR 211.63, 211.67. 52 See 21 CFR 211.46(b), 211.56. 10 Contains Nonbinding Recommendations Draft -- Not for Implementation 366 Manufacturers should periodically identify microorganisms present in the 367 manufacturing facility which might lead to contamination of the NSD, and ensure 368 that their controls effectively mitigate the impact of these microorganisms on their 369 NSD. 370 371 o Equipment: It is important to maintain the sanitary condition of equipment by 372 limiting bioburden through proper design (e.g., vessels, piping), maintenance, 373 cleaning, and sanitization. 374 375 o Cleaning and Sanitizing Agents: Manufacturers must use cleaning/sanitizing 376 agents appropriate to assure that buildings and facilities are maintained in a clean 377 and sanitary manner, which should include ensuring that they do not harbor 378 objectionable microorganisms. 53 Appropriate equipment cleaning is essential to 379 prevent objectional microbiological contamination of components, containers, 380 closures, packaging materials, and drugs. 54 381 382 o Personnel: Manufacturers should take steps to establish and maintain appropriate 383 practices to minimize the potential impact of personnel introducing objectionable 384 microorganisms into the manufacturing process. They must ensure that personnel 385 follow good hygiene practices.55 386 387 o In-Process Testing: Manufacturers are required to establish procedures to assure 388 the quality of in-process materials is consistent with the finished product's 389 established specifications, which includes evaluating whether microbial attributes 390 are met during processing.56 391 392 o Microbiological Release Testing (as appropriate): 393 Total microbial content (microbiological enumeration testing)57 394 Specified organism testing and identification program to identify other 395 objectionable microorganisms58 396 397 53 See 21 CFR 211.56. 54 See 21 CFR 211.56, 211.67. 55 See 21 CFR 211.28(b). 56 See 21 CFR 211.110(a)(6). 57 USP <61> MICROBIOLOGICALEXAMINATION OF NONSTERILE PRODUCTS: MICROBIAL ENUMERATION TESTS. 58 USP <62> MICROBIOLOGICALEXAMINATION OF NONSTERILE PRODUCTS: TESTS FOR SPECIFIED MICROORGANISMS. 11 Contains Nonbinding Recommendations Draft -- Not for Implementation 398 C. Microbiological Concerns for Specific Dosage Forms and Special Cases 399 400 1. Solid Dosage Forms 401 402 Compared to other NSDs, solid dosage forms represent a lower microbiological risk to patients 403 due to their low water activity. Therefore, the microbiological controls associated with their 404 manufacture are generally not expected to be as stringent as those associated with the 405 manufacture of other NSDs. 406 407 The microbiological quality of the finished solid dosage form is also monitored through finished 408 product testing.59 Microbial enumeration testing of the finished drug product can be performed 409 by methods described in the USP for Total Aerobic Microbial Counts (TAMC), Total Combined 410 Yeast and Mold Count (TYMC), and specified organisms, as appropriate.60,61 If testing is 411 performed using compendial methods, method suitability testing should be performed using the 412 drug product. Other test methods, including rapid microbiological methods, may be used for 413 product testing, but will require validation to demonstrate their suitability and equivalence to the 414 compendial methods.62 415 416 Although the USP contains recommended acceptance criteria for microbial control, and specifies 417 the absence of certain objectionable microorganisms,63 manufacturers may develop alternative 418 approaches to microbiological control, including limits/release criteria. For example, many 419 finished solid oral dosage forms have a water activity that does not permit growth or persistence 420 of many vegetative cells. Therefore, it is possible that water activity determination during 421 product development, in conjunction with in-process controls designed to limit objectionable 422 microorganisms, can serve as justification for the reduction or elimination of microbiological 423 testing for release of certain types of solid oral finished products. If there are sufficient data to 424 demonstrate that in-process microbiological controls are successful, finished product water 425 activity is acceptable, and component lot bioburden test results remain consistently in control, 426 the microbial enumeration testing of the finished product may be reduced or eliminated (see 427 section below titled "Potentially Reducing Microbiological Release Testing for Solid Dosage 428 Forms Based on Risk-Based Impact Assessment"). If such surrogate criteria are used in lieu of a 429 product release test, it is important to establish and document appropriate process and facility 430 controls, including testing of incoming component lots and controls in the manufacturing 431 process, as these controls serve to limit the bioburden in the final product. 432 433 59 See 21 CFR 211.165(b). 60 USP <61> MICROBIOLOGICALEXAMINATION OF NONSTERILE PRODUCTS: MICROBIAL ENUMERATION TESTS. 61 USP <62> MICROBIOLOGICALEXAMINATION OF NONSTERILE PRODUCTS: TESTS FOR SPECIFIED MICROORGANISMS. 62 See 21 CFR 211.194(a)(2). 63 USP <1111> MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS: ACCEPTANCE CRITERIA FOR PHARMACEUTICAL PREPARATIONS AND SUBSTANCES FOR PHARMACEUTICAL USE. 12 Contains Nonbinding Recommendations Draft -- Not for Implementation 434 Potentially Reducing Microbiological Release Testing for Solid Dosage Forms Based on Risk- 435 Based Impact Assessment 436 437 Solid dosage forms with a water activity that will not support vegetative microbial growth are 438 excellent candidates for reduced microbial testing for product release and stability. ICH Q6A 439 Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: 440 Chemical Substances includes recommendations for conditions under which "periodic or skip 441 testing" with regard to microbial enumeration testing may be considered. The recommendations 442 in ICH Q6A are based on product characteristics and provide a logical approach to determining 443 an appropriate microbiological testing schedule. To support the reduction or elimination of 444 microbiological release testing for solid dosage forms, manufacturers should conduct a risk- 445 based impact assessment, as recommended in section IV.B of this guidance. 446 447 Microbiological testing in a stability program may be reduced or eliminated for lower risk solid 448 dosage forms with appropriate justification, including the manufacturer's historical experience in 449 manufacturing the NSD, such as the amount of microbiological release and stability data, any 450 adverse findings, and the extent of process, facility, and component bioburden controls. Note that 451 some solid dosage forms that contain growth-supporting components, such as proteinaceous 452 components,64 should undergo a risk assessment to determine if they are candidates for reducing 453 or eliminating the need for microbiological testing in stability protocols. 454 455 2. Non-Solid Dosage Forms 456 457 Typically, non-solid dosage forms (e.g., solutions, suspensions, lotions, creams, and some 458 ointments) have higher water activity than solid dosage forms and thus a higher risk of 459 supporting microbial growth. The capacity of non-solid dosage forms to support microbial 460 growth is largely dependent on the water activity of the drug product components. Many 461 contamination events have been associated with products with water activity levels that support 462 microbial growth, and therefore we recommend that non-solid dosage form manufacturers focus 463 on microbiological quality when evaluating the overall manufacturing process. Understanding a 464 product's water activity throughout the manufacturing process can aid in decisions related to 465 manufacturing, in-process holding times, and storage conditions. For products, components, and 466 in-process materials with water activities that are known to support microbial proliferation, 467 greater scrutiny should be placed on process controls throughout the operation. This includes in- 468 process and finished product microbiological monitoring methods and acceptance criteria, 469 validation of in-process holding periods, 65 and any manufacturing step that is vulnerable to 470 microbial proliferation. For example, naturally occurring ingredients with low water activity may 471 have high intrinsic bioburdens and require special attention. Also, the presence of objectionable 472 microorganisms in the manufacturing steps for topical drugs has resulted in microbial 473 contamination of such products, which typically have low water activity. Additionally, 474 suspensions can present an additional challenge in managing objectionable microorganisms.66 475 Product stability studies should take into account that suspensions may separate into different 64 Solid oral dosage forms with certain naturally-derived active ingredients (e.g., pancreatic enzymes) and soft gelatin capsules havea higher likelihood of harboring objectionable contamination. 65 See 21 CFR 211.111. 66 See footnote 6. 13 Contains Nonbinding Recommendations Draft -- Not for Implementation 476 phases, during storage and distribution, that may result in the segregation of formulation 477 ingredients and cause an unequal distribution of preservatives. The phase with insufficient 478 preservatives may have high water activity resulting in microbial growth. 479 480 In addition to evaluating the overall manufacturing process, it is also important to ensure that 481 manufacturing equipment is cleaned and maintained such that water residue does not remain on 482 equipment while it is stored, unused, or unprotected.67 Water residue can promote microbial 483 growth. Equipment surfaces, including those that may not contact product directly, should be 484 dried or stored in manner that permits rapid drying as soon as possible after cleaning and 485 sanitization. 486 487 Non-solid products with low water activities nonetheless can harbor objectionable contamination 488 due to introduction of contamination during manufacturing or from raw materials. However, 489 microbial proliferation during shelf-life is less common. For non-solid products with synthetic 490 components and water activities that are well below those that are known to support microbial 491 proliferation, less frequent microbiological testing conducted in the finished product stability 492 program may be supportable. Batches placed in a stability testing program are typically sampled 493 and tested at multiple time points over their labeled shelf life, including beginning and end and 494 several interim points. To support reduced (i.e., fewer stability time points) microbiological 495 testing of finished product lots in the stability program, a risk-based impact assessment should be 496 performed that includes water activity data, microbiological monitoring information related to 497 the manufacturing process, bioburden potential of the components, manufacturing history (with 498 attention to any failures and deviations), and an understanding of the processing steps that may 499 contribute positively or negatively to microbiological quality (see previous subsection on 500 "Potentially Reducing Microbiological Release Testing for Solid Dosage Forms Based on Risk- 501 Based Impact Assessment"). 502 503 3. Microbiological Consideration Special Cases 504 505 This section discusses examples of NSD product formulations and intended uses that inherently 506 pose greater relative risk for objectionable microorganisms or bioburden to harm the patient 507 population (e.g., administration of NSD to skin prior to medical procedures that break the skin). 508 This example demonstrates that more rigorous identification and assessment of the bioburden in 509 these products is critical to understand product hazard. Appropriate laboratory methods must be 510 used, and qualified staff must review the results to determine if the product is contaminated with 511 objectionable microorganisms.68,69 These methods should differentiate and identify objectionable 512 microorganisms. Such batch quality information is critical to prevent distribution of an 513 objectionably contaminated product that poses a hazard to consumers, and to facilitate an 514 investigation of the cause(s) to correct or prevent a quality problem. 515 516 67 See 21 CFR 211.67. 68 See 21 CFR 211.160(b). 69 See 21 CFR 211.25(a). 14 Contains Nonbinding Recommendations Draft -- Not for Implementation 517 a. Burkholderia cepacia Complex and Aqueous Drug Products 518 519 Non-sterile aqueous drug products have the potential to be contaminated with BCC organisms 520 because of the potential for these microorganisms to be present in pharmaceutical water systems. 521 (Refs. 2, 18, 19, 21). Burkholderia cepacia is now considered part of a complex of at least 17 522 genomovars, or closely related species (Refs. 2, 8, 14). 523 524 These organisms are opportunistic human pathogens that can cause severe life-threatening 525 infections (Refs. 2, 14, 24). It is important that non-sterile aqueous drug products not contain 526 BCC organisms because of their unique characteristics and the safety risk they pose. BCC strains 527 have a well-documented ability to utilize a wide variety of substrates as energy sources, many of 528 which are traditional preservative systems (Refs. 1-4, 12, 13). Thus, despite the presence of an 529 otherwise adequate preservative system in a non-sterile drug product, BCC strains can survive 530 and proliferate in a non-sterile product over its shelf life. While microbial enumeration testing 531 for finished product release may demonstrate an acceptable level for the total aerobic microbial 532 count, BCC can proliferate to unsafe levels by the time the product reaches the patient. In May 533 2016, the FDA was notified by the Centers for Disease Control and Prevention (CDC) of severe 534 illnesses and deaths associated with BCC in patients in 13 hospitals across 9 states. This 535 prompted the recall of a non-sterile OTC liquid stool softener due to BCC contamination (Ref. 536 17). In a series of cases from 2000 to 2002, involving a medical device (an ultrasound gel), 537 intrinsic contamination by BCC led to serious blood infections after the gel was used in 538 association with transrectal prostate biopsies (Ref. 6). 539 540 Pharmaceutical water and naturally-derived components used in the manufacturing process are 541 the most likely sources of BCC in drug products. Therefore, a robust implementation of the 542 CGMPs is essential to ensure product quality and patient safety, including: 543 544 · establishing a risk management program for the design and control of operations to 545 prevent BCC contamination70 546 · using robust water systems71 547 · ensuring components meet appropriate specifications for bioburden 72 548 · appropriately sanitizing and cleaning equipment,73 and 549 · validated sampling procedures 74 to routinely perform in-process monitoring and finished 550 product testing for the presence of BCC 551 552 Unless a manufacturer performs validated manufacturing steps (e.g., microbial retentive filtration 553 of the bulk product formulation with a sterilizing filter right before filling) that render a drug 554 product free from BCC, release testing is essential as the last in a series of controls that helps 555 demonstrate that the non-sterile aqueous drug product is free from BCC (Ref. 7). 556 70 See 21 CFR 211.100(a), 21 CFR 211.113(a). 71 See 21 CFR 211.42(a). 72 See 21 CFR 211.80(a), 211.84(d)(6). 73 See 21 CFR 211.67(a). 74 See 21 CFR 211.110(a), 21 CFR 211.165(a). 15 Contains Nonbinding Recommendations Draft -- Not for Implementation 557 The USP provides a compendial test for BCC that became official on December 1, 2019, entitled 558 60 MICROBIOLOGICAL EXAMINATION OF NONSTERILE PRODUCTS--TESTS FOR 559 BURKHOLDERIA CEPACIA COMPLEX. FDA recommends that manufacturers use the USP 560 method described in this USP chapter to test drug products for the presence of BCC. If a 561 manufacturer chooses to develop an alternative in-house method, the alternative method or 562 procedure must be fully validated and must produce comparable results to the compendial 563 method.75 Additionally, any applicant choosing to develop an alternative method should be 564 aware that test methods can be complicated by the fact that BCC are highly adaptable and 565 variable in their ability to survive and grow in a variety of environments (Refs. 1, 8). There can 566 be difficulties detecting and correctly identifying and classifying BCC (Refs. 1, 15) and, 567 consideration of the diverse phenotypes exhibited by BCC members is essential for recovery 568 method development (Ref. 3). 569 570 b. Preoperative Skin Preparation Drug Products (Topical 571 Antiseptics) 572 573 Patient preoperative skin preparations are topical antiseptic drug products used to reduce the 574 number of microorganisms on the skin prior to medical procedures or injections, as the skin is 575 typically covered with microorganisms (Ref. 16). Some of these products are not manufactured 576 as sterile products (Ref. 16). However, there have been a number of published reports of 577 infection outbreaks associated with antiseptic products due to microbial contamination (Refs. 9, 578 10, 11, 21). Notably, contaminated antiseptic products made up a majority of non-sterile product 579 recalls that occurred between 2009 and 2013. There were eight recalls due to microbial 580 contamination of alcohol or povidone-iodine prep pads. 581 582 The product indication alone (application to a body surface that is about to be surgically 583 compromised), as well as recent infection outbreaks and product recalls, suggest that the sterility 584 of the product may be an important risk mitigation or have an important impact on clinical 585 outcomes. In 2011, the FDA published a news release reminding health care professionals to 586 check the labeling on alcohol prep pads to determine if they are sterile or non-sterile due to 587 recent contamination events.76 FDA recommended that only sterile pads be used for procedures 588 requiring strict sterility measures (Ref. 19). FDA encourages manufacturers of patient pre- 589 operative antiseptic products to explore manufacturing processes for these products that render 590 them sterile, whether the product is under development or currently marketed. FDA welcomes 591 questions regarding development of sterilization processes for these products, and is committed 592 to working with applicants and other stakeholders on options for sterilization of pre-operative 593 antiseptic products.77 594 75 See 21 CFR 211.194(a)(2), 21 CFR 211.194(a)(6), USP <1223>. 76 FDA Press Announcement "FDA reminds health care professionals about safe use of non-sterile alcohol prep pads," February 1, 2011, https://wayback.archiveit.org/7993/20170113073826/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm241750.htm. See also "FDA Drug Safety Communication: FDA requests label changes and single-use packaging for some overthe-counter topical antiseptic products to decreaserisk of infection," November 13, 2013, https://www.fda.gov/Drugs/DrugSafety/ucm374711.htm. 77 Requests not associated with a specific application can be sent to CDER-OPQ-Inquiries@fda.hhs.gov. 16 Contains Nonbinding Recommendations Draft -- Not for Implementation 595 c. Transdermal Products 596 597 Traditional transdermal and topical delivery systems (collectively TDS) pose limited microbial 598 risk when used on intact skin.78 However, as the technology for these products continues to 599 evolve, the potential risk to patients should be re-assessed to determine the need for additional 600 manufacturing controls. 601 602 TDS designed with a physical mechanism to abrade or penetrate the skin increase the potential 603 for infections, especially given that skin thickness varies across individuals, body sites, and by 604 patient age. During development manufacturers of such TDS should consider the risks and 605 determine whether the TDS should be manufactured as sterile or with a bioburden level below 606 that normally seen with TDS designs that rely on chemical permeation enhancers.79 The FDA 607 encourages these manufacturers to contact the Agency in the early phase of planning and product 608 development.80 609 610 D. Updating Approved Drug Product Specifications 611 612 FDA does not expect application holders of approved drug products to amend the product 613 specification in cases where it is inconsistent with the recommendations discussed in this 614 guidance. If a new supplemental application proposing a manufacturing change that may impact 615 the risk of increased microbiological growth (e.g., new manufacturing process, relaxation of 616 critical process parameters) is submitted, FDA assessors may request that application holders 617 update the microbiological testing information in the product specification during assessment 618 and before approval. Application holders may wish to consider updating a given drug product 619 specification as recommended in this guidance. This could help to expedite approval of future 620 supplements for other manufacturing changes.81 Table 1 provides guidance regarding the filing 621 category for submission of supplements that propose changes to the microbiological testing 622 program of non-sterile drug products. 623 624 78 Technical considerations (beyond microbiological aspects) for traditional transdermal systems are addressed in FDA's draft guidance for industry Transdermal and Topical Delivery Systems - Product Development and Quality Considerations (November 2019). When final, this guidance will represent theFDA's current thinking on this topic. 79 See FDA's guidance for industry Chronic Cutaneous Ulcer and Burn Wounds -- Developing Products for Treatment (June 2006). 80 When the submission is for an NDA, contact the specific drug product's review division with questions. When the product under development is an ANDA, the Office of Pharmaceutical Quality (OPQ) and Office of Generic Drugs (OGD) may be contacted through general correspondence, controlled correspondence, or request for a Pre-ANDA Meeting, as applicable. 81 FDA also recommends that non-application drug products consider updating drug product specifications as maintained by the pharmaceutical quality system as recommended in this guidance. 17 Contains Nonbinding Recommendations Draft -- Not for Implementation 625 Table 1. Regulatory Filing Strategy for Proposed Changes to the Microbiological Testing of 626 Non-Sterile Drugs 627 Proposed Testing Change Regulatory Filing Related Guidance Currently not performing Annual Report Guidance for industry on CMC microbial enumeration testing. Proposing to add testing according to USP General Chapters <61> and <62> with Postapproval Manufacturing Changes To Be Documented in Annual Reports criteria consistent with USP General Chapter <1111>. Currently performing microbial enumeration testing with less stringent acceptance criteria than that suggested in USP General Annual Report Guidance for industry on CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports Chapter <1111>. Proposing to tighten acceptance criteria to USP recommended levels. Currently performing microbial Prior Approval Guidance for industry on Changes to an enumeration testing. Proposing to Supplement Approved NDA or ANDA delete microbial enumeration testing based on submission of a risk assessment. This type of proposal would only be (PAS) appropriate for testing and evaluation of certain solid dosage forms with a low water activity. Currently testing according to Changes Being USP General Chapters <61> and Effected (CBE- <62> with criteria consistent with 0) Guidance for industry on Changes to an Approved NDA or ANDA USP General Chapter <1111>. Proposing to add BCC test, but currently not performing testing for BCC. 628 629 18 Contains Nonbinding Recommendations Draft -- Not for Implementation 630 References (as related to case studies in lines 509-579) 631 632 1. Halls N, 2006, Burkholderia (Pseudomonas) cepacia-A brief profile for the pharmaceutical 633 microbiologist, Eur J Parenteral and Pharm Sci, 11(2):53-57. 634 2. Vial L, A Chapalain, MC Groleau, and E Desiel, 2011, The various lifestyles of the 635 Burkholderia cepacia complex species: a tribute to adaptation, Environ Microbiol, 13(1):1- 636 12. 637 3. Zani F, A Minutello, L Maggi, P Santi, and P Mazza, 1997, Evaluation of preservative 638 effectiveness in pharmaceutical products: the use of a wild strain of Pseudomonas cepacia, J 639 Appl Microbiol, 83(3):322-326. 640 4. Amin A, S Chauhan, M Dare, and AK Bansal, 2010, Degradation of parabens by 641 Pseudomonas beteli and Burkholderia latens, Eur J of Pharm and Biopharm, 75:206-212. 642 5. Hutchinson J, W Runge, M Mulvey, G Norris, M Yettman, N Valkova, R Villemur, and F. 643 Lapine, 2004, Burkholderia cepacia infections associated with intrinsically contaminated 644 ultrasound Gel: The role of microbial degradation of parabens, Infect Cont Hosp Epid, 645 25:291-296. 646 6. Torbeck L, D Raccasi, DE Guilfoyle, RL Friedman, D Hussong, 2011, Burkholderia cepacia: 647 This Decision is Overdue, PDA J Pharm Sci Tech, 65(5):535-43. 648 7. Ahn Y, JM Kim, H Ahn, Y-J Lee, JJ LiPuma, D Hussong, and CE Cerniglia, 2014, 649 Evaluation of liquid and solid culture media for the recovery and enrichment of Burkholderia 650 cenocepacia from distilled water, J Indus Micro and Bio, 41(7):1109-1118. 651 8. Chang CY and LA Furlong, 2012, Microbial Stowaways in Topical Antiseptic Products, N 652 Engl J Med, 367(23):2170-2173. 653 9. Notes from the Field: Contamination of Alcohol Prep Pads with Bacillus cereus Group and 654 Bacillus species--Colorado, 2010, MMWR Morb Mortal Wkly Rep 2011 60(11):347. 655 10. Sutton S and L Jimenez, 2012, A Review of Reported Recalls Involving Microbiological 656 Control 2004-2011 with Emphasis on FDA Considerations of Objectionable Organisms, Am 657 Pharm Rev, Jan/Feb:42-56. 658 11. Burdon DW and JL Whitby,1967, Contamination of hospital disinfectants with Pseudomonas 659 species, Brit Med J, 2:153-155. 660 12. Geftic SG, H Heymann, and FW Adair, 1979, Fourteen-Year Survival of Pseudomonas 661 cepacia in a Salts Solution Preserved with Benzalkonium Chloride, App and Env Micro, 662 37(3):505-510. 663 13. Mahenthiralingam, E, TA Urban, and JB Goldberg, 2005, The multifarious, multireplicon 664 Burkholderia cepacia complex, Nature Reviews Microbiology, 3(2):144156. 665 14. Lowe P, C Engler, and R Norton, 2002, Comparison of Automated and Nonautomated 666 Systems for Identification of Burkholderia pseudomallei, J Clin Micro, 40(12):4625-4627. 667 15. Federal Register/Vol 77, No 225/Wednesday, November 21, 2012/Notices FDA-2012-N- 668 1040, https://www.govinfo.gov/content/pkg/FR-2012-11-21/pdf/2012-28357.pdf. Antiseptic 669 Patient Preoperative Skin Preparation Products; Public Hearing. 670 16. FDA Updates on Multistate Outbreak of Burkholderia cepacia Infections, October 12, 2016, 671 http://www.fda.gov/Drugs/DrugSafety/ucm511527.htm. 672 17. Carson LA, MS Favero, WW Bond, and NJ Petersen, 1973, Morphological, Biochemical, 673 and Growth Characteristics of Pseudomonas cepacia from Distilled Water, App Micro, 674 25(3):476-483. 19 Contains Nonbinding Recommendations Draft -- Not for Implementation 675 18. Jimenez L, 2007, Microbial Diversity in Pharmaceutical Products Recalls and Environments, 676 Parenteral Drug Association J of Pharm Sci and Tech, 61(5):383-399. 677 19. FDA News Release, FDA Reminds Healthcare Professionals about Safe Use of Non-Sterile 678 Alcohol Prep Pads, February 1, 2011. 679 20. Halls N, Burkholderia (Pseudomonas) cepacia A brief profile for the pharmaceutical 680 microbiologist, EJ Parenteral & Pharmaceutical Sci, 11(2):53-57. 681 21. Webber D, W Tutella, E Sickbert-Bennet, Outbreaks associated with contaminated 682 antiseptics and disinfectants, Antimicrobial Agents and Chemotherapy, Dec 2007. 683 22. Micronase Tablets Recalled Fungal Organisms Found In Anti-Diabetic Medication (traced to 684 a raw material used in the formulation. Micronase is an oral antidiabetic medication used to 685 treat type 2 diabetes). https://www.fda.gov/inspections-compliance-enforcement-and- 686 criminal-investigations/warning-letters/ctx-lifesciences-private-ltd-577416-07122019. 687 23. Nationwide recall for 2 lots Relpax 40 Mg Tablets Due to Potential Microbiological 688 Contamination of Non-Sterile Products https://www.fda.gov/safety/recalls-market- 689 withdrawals-safety-alerts/pfizer-inc-issues-voluntary-nationwide-recall-2-lots-relpaxr- 690 eletriptan-hydrobromide-40-mg-tablets. 691 24. Glowicz J, M Crist, C Gould, H Moulton-Meissner, J Noble-Wang, T de Man, A Perry, Z 692 Miller, W Yang, S Langille, J Ross, B Garcia, J Kim, E Epson, S Black, M Pacilli, J LiPuma, 693 R Fagan, 2018, A multistate investigation of healthcare-associated Burkholderia cepacia 694 complex infections related to liquid docusate sodium contamination, January - October 2016, 695 Am J Infect Control. 2018 Jun; 46(6): 649655. https://pubmed.ncbi.nlm.nih.gov/29329922/ 696 697 20 Contains Nonbinding Recommendations Draft -- Not for Implementation 698 APPENDIX: Case Study Examples of Microbiological Contamination of NSD Products; 699 Impact on Product Quality and Manufacturing Process 700 701 The following seven case studies summarize incidents of NSDs contaminated with 702 microorganisms leading to infections, and ultimately product recalls. In each of the cases below, 703 the manufacturer of the product initiated voluntary recall actions to mitigate the impact of the 704 contaminated product on patients and end-users, and instituted new processes and corrective 705 measures to prevent future microbial contamination of their product. Of particular significance 706 are the root cause analyses and corrective/preventative strategies that manufacturers took to 707 address microbiological contamination. These examples suggest that risk assessments should be 708 an integral part of strategies to prevent the microbiological contamination of NSDs. 709 710 Case 1: Contamination of an oral solution with Burkholderia cepacia complex (BCC) 711 712 In 2016, an OTC product (oral liquid docusate sodium) indicated for constipation was contract 713 manufactured for a customer who marketed the products under its own label. FDA investigated a 714 multistate outbreak of serious BCC infections in 108 patients, including multiple associated 715 patient deaths. Testing by FDA and CDC revealed that more than 10 lots of oral liquid product 716 were contaminated with BCC. The BCC clinical isolates matched with the product isolates. The 717 investigation also detected BCC in the water system used by the firm to manufacture the product. 718 FDA and CDC identified the contract manufacturer as the source of the outbreak. The poorly 719 designed water system (cold system; not continuously circulating), inadequate monitoring of the 720 system, poor manufacturing controls, and inadequate microbiological testing methods all 721 contributed to severe risks to the consumer. All lots of liquid products made by the contract 722 manufacturer were ultimately recalled. 723 724 Case 2: Contamination of aqueous-based throat spray and liquid antacid with Escherichia 725 coli 726 727 In 2014, a manufacturer of an aqueous-based, non-sterile spray to relieve throat dryness and to 728 restore throat comfort was determined to be contaminated with Escherichia coli (E.coli). The 729 contamination was discovered when a microbial assay of the product returned results that 730 indicated the bacterial count to be too numerous to count (TNTC). Although the root cause was 731 not fully determined by the firm, several manufacturing practices were corrected as a result of 732 the event, including new processes and procedures for cleaning and storage of equipment, and 733 physical separation between used equipment and equipment that had been sanitized. Over 20,000 734 units of this product were distributed nationally. 735 736 A separate case of E.coli contamination of an antacid liquid occurred in 2013, in which over 737 10,000 units of the contaminated product were distributed nationally prior to completion of 738 quality assurance testing. When the microbial assay for the product returned with E.coli counts 739 greater than 3000 CFU/g, the product was immediately recalled by the manufacturer. After the 740 manufacturer's investigation, the quality assurance procedures were updated and employee 741 training was conducted. However, the root cause of the contamination was not determined. In 742 this instance, there were no reported injuries or illnesses that were attributed to the contaminated 743 product. 21 Contains Nonbinding Recommendations Draft -- Not for Implementation 744 745 A review of FDA's recall database between 2012 and 2017 demonstrates that at least four other 746 separate events have occurred with non-sterile aqueous based products resulting in E. coli 747 contamination. 748 749 Case 3: Contamination of moisturizing cream with Pseudomonas and Staphylococcus 750 751 In 2017, a manufacturer of a baby eczema moisturizing cream reported that their product was 752 contaminated with Pseudomonas aeruginosa and Staphylococcus aureus. Over 15,000 units of 753 the product were distributed nationally. The microbial assay determined that the bacterial load in 754 the products was 87,500 CFU/g, despite presence of a preservative in the formulation. The root 755 cause for the microbiological contamination appeared to be a raw material of natural origin that 756 became contaminated due to improper storage at the firm, and apparently resulted in 757 microbiological growth in finished product. 758 759 Similarly, in 2015, a distributor of a liquid antacid determined that over 100,000 units of their 760 nationally distributed product was objectionably contaminated. Product contamination included 761 Pseudomonas aeruginosa, as well as high yeast and mold counts. The recall scope was based on 762 assessment of retention samples spanning 12 months. The root cause of the contamination 763 appeared to be related to issues in the contract manufacturing process, but the ultimate root cause 764 was not identified. 765 766 Case 4: Excessive contamination of a non-aqueous-based cream indicated for infants 767 768 In 2018, a zinc oxide diaper rash cream, indicated for infants, was imported by a US distributor 769 who intended to market it as an OTC product. When tested, it was found to be objectionably 770 contaminated. Although the product was not aqueous-based, and had a low intrinsic water 771 activity, it contained excessive numbers of bacteria and fungi. Samples included units with 772 several very high aerobic microbial counts including values such as 3.5 million CFU Total 773 Aerobic Microbial Count (TAMC)/mL and 27,000 CFU TAMC/mL. Many of the bacteria were 774 spore formers of the Bacillus, spp. Yeast and mold count levels were also very high, including 775 2700 Total Combined Yeast and Mold Count (TYMC)/mL, 39000 TYMC/mL, and 200 776 TYMC/mL. The manufacturer recalled all lots of the product and ceased shipping to the US. 777 778 Case 5: Topical cream contaminated with Enterobacter, sp. 779 780 In 2018 a manufacturer of a topical cream-based drug became aware that several lots of their 781 product were contaminated with Enterobacter, sp. The product was inadvertently shipped prior 782 to the completion of the microbial assay, which resulted in a microbial count that was TNTC. In 783 addition to the assay, there was an unusually strong odor not typically associated with the 784 product. After the recall was initiated, the manufacturer received customer complaints regarding 785 a strong odor from the product. The potential root cause for the microbiological contamination 786 was suspected to be improper changeover cleaning of the filling equipment. Several corrective 787 actions were taken to prevent future microbial contamination of product, including revision of 788 preventative maintenance and release testing procedures and employee re-training. 789 22 Contains Nonbinding Recommendations Draft -- Not for Implementation 790 791 Case 6: Alcohol antiseptics contaminated with Bacillus cereus 792 793 In 2011, an alcohol-based antiseptic product was produced under poor manufacturing conditions 794 and the product was found to be contaminated with Bacillus, spp., including Bacillus cereus. 795 Adverse events were reported to be associated with the contaminated antiseptics. Inspection of 796 the firm found lack of appropriate controls to prevent contamination during formulation, filling, 797 and storage of the drug products. Equipment was also observed to be insufficiently cleaned. 798 These deficient conditions likely contributed to the contamination events. The manufacturer 799 issued a voluntary nationwide recall of all lots of alcohol prep pads, alcohol swabs, and alcohol 800 swab sticks, due to confirmed and potential microbial contamination. 801 802 Case 7: Contamination of an API with Aspergillus, sp. and Enterobacter, sp. 803 804 In 2016, a manufacturer of an API that is further utilized by other manufacturers to derive oral 805 and injectable finished pharmaceuticals became aware of customer complaints that their API 806 contained TNTC/g levels of fungal contamination by various Aspergillus species. The root cause 807 for this microbiological contamination appeared to be related to parts of the drying equipment 808 used to dry the API. As corrective action, the API manufacturer replaced defective drying 809 equipment ductwork to prevent trapped moisture from collecting within it, and revised existing 810 preventive maintenance/monitoring procedures to enable a more robust control against 811 microbiological contamination. The API manufacturer initiated a voluntary recall that impacted 812 several API lots over the course of one year, and several manufacturers of finished drug 813 products. There were no reported injuries or illnesses associated with the contaminated product. 814 815 In 2014, another manufacturer of a bulk cream base used to compound topical drugs recalled 816 several lots of its bulk cream due to high counts of mold and bacteria, and specifically high 817 counts of Aspergillus, sp. and Penicillium, sp. (among other microorganisms). The root cause of 818 the microbial growth was insufficient manufacturing instructions that resulted in personnel 819 adding lower amounts of preservatives than needed to ensure uniform distribution throughout 820 each of the affected batches. When the final products were manufactured, enclosing the cream in 821 its final container/closure resulted in the development of moisture as the product cooled. The 822 moisture enabled mold to grow. Microbial assays of impacted lots all demonstrated mold growth, 823 and corresponding microbial identity testing demonstrated lower preservative amounts in 824 impacted batches. To mitigate future errors, the bulk cream manufacturer modified their 825 manufacturing procedures and processes to ensure uniform distribution of the preservatives in 826 each bulk cream batch. 827 828 Case 8: Fungal contamination traced to excipient 829 830 In 2001, a manufacturer recalled 45 lots of Glyburide tablets for fungal contamination. The 831 source of the contamination was traced to a filler/binder excipient used in the formulation. A 832 subsequent FDA Warning Letter cited the firm for not conducting an adequate investigation to 833 determine the sources of the fungal contaminants and identify other Glyburide tablet lots 834 manufactured which used the same excipient lots as well as the failure to appropriately sample 835 and test the excipient. Additional investigation found that the air used in the drying process of 23 Contains Nonbinding Recommendations Draft -- Not for Implementation 836 the excipient was contaminated with seasonal fungal spores during the chemical synthesis of 837 excipient at the excipient manufacturing facility. 838 839 Case 9: Contamination of eletriptan hydrobromide with Pseudomonas, sp. and 840 Burkholderia, sp. 841 842 In 2019, a firm recalled two lots of eletriptan hydrobromide because these product lots failed 843 microbiological specifications for the potential presence of Pseudomonas, sp. and Burkholderia, 844 sp. For the general population these risks are low, and may include temporary gastrointestinal 845 distress without serious infection. However, for certain vulnerable patient populations (such as 846 patients with compromised immune systems, cystic fibrosis and chronic granulomatous disease) 847 this objectionable contamination may pose the potential for serious adverse events including life848 threatening infections. 849 24Young, Grant Adobe PDF Library 11.0