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HANDBOOK OF PHARMACEUTICAL MANUFACTURING FORMULATIONS VOLUME 6 PDF

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Boca Raton London New York Washington, D.C.. HANDBOOK OF. Pharmaceutical. Manufacturing. Formulations. Sterile Products. Sarfaraz K. Niazi. VOLUME 6. Volume 6. Handbook of Pharmaceutical Manufacturing Formulations: . PDF). scale-up and postapproval a regulatory review. changes. and special topical. International Standard Book Number (Volume 6; Handbook of pharmaceutical manufacturing formulations / Sarfaraz K.


Handbook Of Pharmaceutical Manufacturing Formulations Volume 6 Pdf

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of pharmaceutical manufacturing formulations second edition volume 3 liquid Volume 6 Handbook of Pharmaceutical Manufacturing Formulations: Sterile. (Vol. 6 of 6) (HANDBOOK OF Pharmaceutical Manufacturing Manufacturing Formulations, Sterile Products (Vol. 6 of 6) .. Download PDF. Handbook of Pharmaceutical Manufacturing Formulations, Sterile Products (Vol. 6 of 6).

N53 '19dc21 This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated.

A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage or retrieval system, without prior permission in writing from the publisher.

The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Corporate Blvd. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation, without intent to infringe. Wagner Preface to the Series No industry in the world is more highly regulated than Each volume includes a description of regulatory fil- the pharmaceutical industry because of potential threats ing techniques for the formulations described.

Also to patients lives from the use of pharmaceutical products. The generic market of drugs as new that have survived the test of time. Many of us who have entities come off patent is one of the fastest growing worked in the pharmaceutical industry suffer from a segments of the pharmaceutical industry, with every major closed paradigm when it comes to selecting formulations; multinational company having a significant presence in not invented here perhaps subconsciously reigns in the this field.

The Handbook of Pharmaceutical Manufac- offers a wealth of information. Whether it is a selection turing Formulations is the first major attempt to consoli- of a preservative system or the choice of a disintegrant, date the available knowledge about formulations in a com- the series offers a wide choice to study and rationalize.

Many have assisted me in the development of this The book is divided into six volumes, based strictly work, which has taken years to compile, and I am thankful on the type of formulation science involved in the develop- to scores of my graduate students and colleagues for their ment of these dosage forms: sterile products, compressed help.

A work of this size cannot be produced without solids, uncompressed solids, liquid products, semisolid errors, though I hope these errors do not distract the reader products, and over-the-counter OTC products. The sep- from the utility of the book. I would sincerely appreciate aration of OTC products, though they may easily fall into readers pointing out these mistakes to me for corrections one of the other five categories, is made to comply with in future editions.

Sterile products require skills related to steril- ization of product, and of less importance is the bioavail- Sarfaraz K. Niazi, Ph. These types of considerations have led to the classification of products into these six categories. Preface to the Volume The semisolid drugs category is comprised of ointments, much of the regulatory discussion presented here is drawn creams, gels, suppositories, and special topical dosage from the requirements of the U.

Food and Drug Admin- forms. The formulations of semisolid drugs share many istration FDA and the harmonized guidelines with the common attributes of consistency, presentation, preserva- ICH listings.

Although it is likely that some of the require- tion requirement, and the route of administration, mainly ments and recommendations made here might change, it topical. As a result, grouping them together for the purpose is unlikely that the basic thrust in establishing these guide- of defining common formulation practices and problems lines will change. As always, the applicants are highly is justified. The topical dosage forms present unique encouraged to communicate with the FDA on the changes opportunities to design novel drug delivery systems such made to these guidelines and especially for any significant as patches and other transdermal systems.

Some of these changes made to compliance requirements. In selecting the formulations, I have tried to drawal and finalization of guidelines provided. PDF , which should be reviewed periodically. Obvi- made to approved NDAs or ANDAs; this is a significant ously, considerations such as incompatability of the drug topic for continued compliance with the CGMP require- with the ingredients is of pivotal importance; these base ments but, unfortunately, the one that is most easily misun- formulations of stable emulsions provide a good starting derstood or misconstrued.

For example, at what level of point in the development of new products or even when change should the FDA be informed, either before making a different topical consistency is desired. I have also made a change or after? What happens if a change is made inad- an effort to highlight those formulations that are currently vertently and later discovered; how to report this change?

The situation have chosen to only give the composition or mere identi- gets extremely complex when there are multiple dosage fication of ingredients to conserve space for those formu- forms, for which the requirements may be different.

Chapter 2 gets into details of changes made pursuant The regulatory agencies impose certain specific to discussion in Chapter 1 when it comes to semisolid requirements on the formulation and efficacy determina- drugs. A more detailed description of level of changes is tion of drugs contained in these formulations. For exam- described here, and advice is provided on when to conduct ple, the CGMP factors, scale-up and postapproval a regulatory review.

The effect of equipment layout and design on the ination or supervisory examination to have an apparentclean-room environment should be addressed. Follow the principle of slow, careful ical personnel not to jeopardize the safety or quality of movement throughout the clean room. All personnel shall be instructed to report 3. Keep the entire body out of the path of laminar to supervisory personnel any health conditions that may air.

Approach a necessary manipulation in a mannerfacilities designated as limited-access areas. To maintain sterility of nearby sterile mate-itoring environmental conditions. Also, speak- ing when in direct proximity to an aseptic pro-A well-designed aseptic process minimizes personnel cessing line is not an acceptable practice.

As operator activities increase in an aseptic 5. It is essential that operators involved in be appropriately gowned. An aseptic process-aseptic manipulations adhere to the basic principles of ing-area gown should provide a barrier betweenaseptic technique at all times to assure maintenance of the body and exposed sterilized materials, andproduct sterility.

Appropriate training should be conducted prevent contamination from particles generatedbefore an individual is permitted to enter the aseptic pro- by, and microorganisms shed from, the body. For example, such Gowns need to be sterile and nonshedding, andtraining should include aseptic technique, clean-room should cover the skin and hair. After initial training, personnel should be ments of gowns. An adequate barrier should beupdated regularly by an ongoing training program. If an elementconformance to written procedures during actual opera- of the gown is found to be torn or defective,tions.

Similarly, the quality control unit should provide change it immediately. There should be anregular oversight of adherence to established, written pro- established program to regularly assess or auditcedures, and basic aseptic techniques during manufactur- conformance of personnel to relevant asepticing operations.

The following are some techniques aimed at main- gowning procedures. Always use sterile instruments e. Following an initial assessment of gown- ceps while handling sterilized materials. Replace these instruments as period to ensure the consistent acceptability of necessary throughout the operation.

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Regularly aseptic gowning techniques. Personnel mated operations where personnel involvement should not directly contact sterile products, con- is minimized. To protect exposed sterilized tainers, closures, or critical surfaces.

Move slowly and deliberately. Rapid move- ments can create unacceptable turbulence in the critical zone. Sterile Products standards in a consistent manner. Laboratory Personnel Section Processes and ination that is objectionable in view of its intended usesystems cannot be considered to be under control and shall be subjected to microbiological tests before use.

A drug product produced by aseptic processing can become contaminated by use of one or more components3. Monitoring Program e. It is important toPersonnel can have substantial impact on the quality of characterize the microbial content of each component lia-the environment in which the sterile product is processed.

Monitoring should be accomplished Knowledge of bioburden is critical in assessing whetherby obtaining surface samples of each aseptic processing the sterilization process is adequate. This sampling should be accompanied In aseptic processing, each component is individuallyby an appropriate frequency of sampling for other strate- sterilized or several components are combined, with thegically selected locations of the gown. There are several methods tounit should establish a more comprehensive monitoring sterilize components.

The solu-complex aseptic manipulations. Asepsis is fundamental to tion is passed through a sterilizing membrane or cartridgean aseptic processing operation. Filter sterilization is used when the component isufacturing personnel in the aseptic processing room is to soluble and is likely to be adversely affected by heat. Sanitizing gloves just prior to sampling is inappro- solution to aseptic crystallization and precipitation of thepriate because it can prevent recovery of microorganisms component as a sterile powder.

However, this methodthat were present during an aseptic manipulation. When involves more handling and manipulation and thereforeoperators exceed established levels or show an adverse has a higher potential for contamination during process-trend, an investigation should be conducted promptly.

Fol- ing. Dry heat sterilization is a suitable methodoutside of the aseptic processing area. Microbiological for components that are heat stable and insoluble.

How-trending systems and assessment of the impact of atypical ever, carefully designed heat penetration and distributiontrends are discussed in more detail under the section on studies should be performed for powder sterilizationlaboratory controls. Such methods should be carefully controlled and1. Components validated if used for powders to evaluate whether consis- tent penetration of the sterilant is achieved and to mini-Section Inspection of Sterile Product Manufacturing Facilities BiologicalSection The time between washing and sterilizing shouldprevent microbiological contamination of drug products be minimized because moisture on the stoppers can sup-purporting to be sterile.

Because rubber is a poor conductor of heat, extra attentiona. Preparation should be given to the validation of processes that use heat to sterilize rubber stoppers.

Validation data should alsoContainers and closures should be rendered sterile and, demonstrate successful endotoxin removal from rubberfor parenteral drug products, pyrogen-free. The type of materials. The A potential source of contamination is the siliconiza-validation study for any such process should be adequate tion of rubber stoppers.

Silicone used in the preparationto demonstrate its ability to render materials sterile and of rubber stoppers should be rendered sterile and not havepyrogen-free. Written procedures should specify the an adverse effect on the safety, quality, or purity of thefrequency of revalidation of these processes as well as drug product. It is important to establish production timetime limits for holding sterile, depyrogenated containers limits for the holding of sterilized containers and closures.

Contract facilities that perform sterilization and depy- Presterilization preparation of glass containers usually rogenation of containers and closures are subject to theinvolves a series of wash-and-rinse cycles. These cycles same cGMP requirements as those established for in-serve an important role in removing foreign matter. Rinse house processing. Anycontent after depyrogenation.

Positive controls should be used to measure the shipment of product that may lack container—closurepercentage of endotoxin recovery by the test method.

Handbook of Pharmaceutical Manufacturing Formulations. Fifth Edition. Six Volumes.

Val- integrity and lead to nonsterility. Validation of dry heat led to drug recalls. If damage that is not readily detectedsterilization or depyrogenation should include appropriate leads to loss of container—closure integrity, improved pro-heat distribution and penetration studies as well as the use cedures should be rapidly implemented to prevent andof worst-case process cycles, container characteristics detect such defects.

Functional defects in delivery devices e. Plastic containers can in-process testing. Sterile ProductsE. Time limits should include, for exam-requirements. Maintenance ofcleaned, maintained, and sanitized at appropriate intervals in-process quality at different production phases should beto prevent malfunctions or contamination that would alter supported by data.

The total time forments. Ster-their intended use. Endotoxin contamination of an injectable product can G. Such clinical concerns reinforce the need for appropriate Such procedures shall include validation of any steriliza-cGMP controls to prevent generation of endotoxin.

Drug tion process. Changeand sterilized. Endotoxin on equipment surfaces is inactivated ment, process, test method, or systems requires evalua-by high-temperature dry heat, or removed from equipment tion through the written change control program andsurfaces by validated cleaning procedures. Process SimulationsWFI. Equipment should be dried following cleaning. SOPs conditions permitted before line clear- Validation of an aseptic processing operation should ance is mandated, etc.

The b. Frequency and Number of Runsresults are interpreted to determine the potential for anygiven unit of drug product to become contaminated during When a processing line is initially validated, separateactual operations e. Environ- results are consistent and meaningful. This approach ismental monitoring data is integral to the validation of an important because a single run can be inconclusive,aseptic processing operation.

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A minimum of three consecutivea. All personnel who enter the aseptic pro-turing operations as closely as possible, incorporating a cessing area, including technicians and maintenance per-worst-case approach.

Sterile Productsc. Size and Duration of Runs e. Adequate batch sizes are needed to simulate in order to support the validity of these studies. The f. The run bean casein digest medium should be used. Use of anaer-should be large enough to accurately simulate production obic growth media e. Media selectedof contaminated units.

Positive controloperation. For instances in which the growth promo-and are designed to limit operator intervention, some pro- tion testing fails, the origin of any contamination foundcesses include considerable operator involvement. The pro-extensive manual manipulations, the duration of the pro- duction process should be accurately simulated usingcess simulation should generally be no less than the length media and conditions that optimize detection of anyof the actual manufacturing process in order to best sim- microbiological contamination.

Some drug manufacturersevacuation of the chamber in a manner that is representa- have expressed concern over the possible contaminationtive of process stresses. Vials should not be frozen, as this of the facility and equipment with the nutrient media dur-may inhibit the growth of microorganisms. However, if the medium is handled properly and is promptly followed by the cleaning, sani-d.

In some cases, g. Incubation and Examination of Media-Filledmore than one line speed should be evaluated in the course Unitsof a study. Use of slow niques. Clear contain-acterized by prolonged exposure of sterile components ers with otherwise identical physical properties should bein the aseptic area.

The microorganismsshould proceed to incubation. In the case of a medianot related to integrity e. Test results should show, with a high degree ofto the market. The purpose of an aseptic process is toshould clearly document conformance with this proce- prevent any contamination. A manufacturer is fully liabledure. FDA also recognizes thatproduction run. Supporting documen-and accountability. Interpretation of Test Results Filtration is a common method of sterilizing drug product solutions.

The microorganisms manufacturing areas. However, it is essential that labora-should be small enough to both challenge the nominal tory experiments simulate actual production conditions. However,mean diameter. The num- ucts. Normally, integrity testing of thetration area of B.

However, directly studies. Sterilization of Equipment andto erroneous conclusions. This step It is as important in asepticantimicrobial preservative or other antimicrobial compo- processing to properly validate the processes used to ster-nent as the vehicle.

Handbook of Pharmaceutical Manufacturing Formulations

Sterility of aseptic processing equipment e. Inspection of Sterile Product Manufacturing Facilities 19a. In some cases, theshould also be performed on a periodic basis.

For both the bioburden-based cycle is used for sterilization validation. When determining which articles are most dif-load. D-value of the bio- on the downstream side. Biological indicators should belogical indicator can vary widely depending on the mate- placed at appropriate downstream locations of this equip-rial e. The formal program providing for regular i. Change control toring devices should be considered to be of utmost impor-procedures should adequately address issues such as a load tance.

Written procedures should be estab- lished to ensure that these devices are maintained in ai. Empty Chamber calibrated state.

Temperature monitoring devices for heatTemperature distribution studies evaluate numerous loca- sterilization should be calibrated at suitable intervals, astions throughout an empty sterilizing unit e. Devices used toautoclave, dry heat oven or equipment train e. It is important that these studies calibrated. Sterilizing equipment should be properly maintained to allow for consistently satisfactory function.

Validation of the sterilization whether the unit continues to operate properly. The placement of biological indi- Section Sterile Productscomponents, drug product containers, closures, in-process Locations posing the most microbiological risk to thematerials, labeling, and drug products conform to appro- product are a critical part of the program. It is especiallypriate standards of identity, strength, quality, and purity.

Critical surfaces which contact sterile product shouldSection Air and surface samples should be taken at the actual Inmaterials to be used in cleaning the buildings and facili- particular, low-level contamination can be particularly dif-ties.

Because of the likelihood of false nega-the contamination of equipment, components, drug prod- tives, consecutive growth results are only one type ofuct containers, closures, packaging, labeling materials, or adverse trend. Increased incidence of contamination overdrug products and shall be followed. Writtenlabeling, shall be reviewed and approved by the quality SOPs should also address areas such as frequency of sam-control unit to determine compliance with all established, pling, when the samples are taken i.

Environmental Monitoring appropriate response to deviations from alert or action limits. General Written Program b. Establishing Limits and a Trending ProgramIn aseptic processing, one of the most important laboratorycontrols is the establishment of an environmental moni- Microbiological monitoring limits should be establishedtoring program.

This monitoring provides meaningful based on the relationship of the sampled location to theinformation on the quality of the aseptic processing envi- operation. The limits should be based on the need toronment when a given batch is being manufactured as well maintain adequate microbiological control throughout theas environmental trends of the manufacturing area. An entire sterile manufacturing facility. Microbiological environmental monitoring should include both alert and action limits.

Averaging of results can maskprogram and validated methods. The monitoring program unacceptable localized conditions. Writ- investigation. Sample timing, frequency, and location should inants, and actions to be taken. The quality control unitbe carefully selected based on their relationship to the should provide routine oversight of near-term e.

Samples should be taken throughout weekly, monthly, or quarterly and long-term trends inthe aseptic processing facility e. Inspection of Sterile Product Manufacturing Facilities 21control unit is responsible for producing specialized data environment during each production shift at carefully cho-reports e. Passive Air Monitoring Settling Plates with any appropriate corrective action promptly imple- Another method is the use of passive air samplers such asmented.

These settling platesinformed and updated on trends and investigations. As part of methodsagents should be assessed with their implementation for validation, the quality control laboratory should evaluateuse in clean areas.

The effectiveness of these sanitization what media exposure conditions optimize recovery of lowprocedures should be measured by their ability to ensure levels of environmental isolates.

Exposure conditionsthat potential contaminants are adequately removed from should preclude desiccation e. On preparation, disinfectants should be ren- microorganisms. Many common sanitizers 2. The environmental monitoring program should includeA sporicidal agent should be used regularly to prevent routine characterization of recovered microorganisms. To detect such trends, an adequate pro- gram of differentiating microorganisms in lesser-con-d. Monitoring Methods trolled environments e.

Surface Monitoring in the facility during processing and to demonstrate thatEnvironmental monitoring should include testing of vari- cleaning and sanitization procedures continue to be effec-ous surfaces for microbiological quality.

For example, tive. Routinely used failure, and the overall environmental picture providesfor such tests are touch plates, swabs, and contact plates.

Other surfaces in controlled areas should be tested to showthe adequacy of cleaning and sanitizing procedures. The goal of microbiological monitoring is to repro- ducibly detect microorganisms for purposes of monitoringii.

Active Air Monitoring the state of environmental control. Consistent methodsThe method of assessing the microbial quality of air will yield a database that allows for sound data compari-should involve the use of active devices such as slit to sons and interpretations. Each device has dated as capable of detecting fungi i. Total aerobic bacterial count canume of air sampled. Where appropriate, inactivating agents Section Certain aspects of sterility testing are of particulara.

The test-bioburden should be minimal. An in-process limit for bioburden level for each trols can result in a high rate of test failures. Particulate Monitoring ratory even when the product tested could have, in fact, been nonsterile. A result outside the false positives. Choice of Methodssion. Sterility testing methodologies are required to be accurate and reproducible, in accord with Section The methodology selected should present the lowest potential for yielding a false positive.

Such testing should demonstrate reproducibil-ments. The test procedures shall be in writing and shall ity of the method in recovering each of a panel of repre-be followed. If growth is inhibited, Such validation and documentation may be tunity for false negatives.

Mediadures be established in order to ensure batch uniformity. A written program should be in as part of testing should a new test be performed. After considering all relevant factors concerning the manufacture of the product and testing of the samples, the4. For example, statistical evalua- contamination should be based on at least the followingtions indicate that the USP sterility test sampling plan factors.

Microbiological monitoring data shouldtest.

This limited sensitivity makes it necessary to ensure be reviewed to determine whether the organism is alsothat for batch release purposes, an appropriate number of found in laboratory and production environments, person-units are tested and that the samples uniformly represent nel, or product bioburden. Samples environment, then product contamination is likely. If the should be taken in conjunction with processing organism is found in laboratory and production environ- interventions or excursions.

Because of the lim- ments, it can indicate product contamination. Proper han- ited sensitivity of the test, any positive result is dling of deviations is an essential aspect of laboratory considered a serious cGMP issue and should be control.

When a deviation occurs during sterility testing, thoroughly investigated. If any deviation is considered to have compromised the5. Investigation of Sterility Positives integrity of the sterility test, the test should be invalidated immediately without incubation. Care should be taken in the performance of the sterilitytest to preclude any activity that allows for possible sam- Deviation and sterility test positive trends should beple contamination.

When microbial growth is observed, evaluated periodically e. It is inap- an overview of operations. A sterility positive result canpropriate to attribute a positive result to laboratory error be viewed as indicative of production or laboratory prob-on the basis of a retest that exhibits no growth.

Under- lems and should be investigated globally because suchscoring this regulatory standard, USP XXV, Section problems often can extend beyond a single batch. If the degree of sterility test sample manipulation is similar for a termi- The evaluation of a positive sterility test result should nally sterilized product and an aseptically processed prod-include an investigation to determine whether the growth uct, a higher rate of initial sterility failures for the latterobserved in the test arose from product contamination or should be taken as indicative of aseptic processing pro-from laboratory error.

Although it is recognized that such duction problems. When and personnel over time can also reveal trends that areavailable evidence is inconclusive, batches should be informative.

Upward trends in the microbial load in therejected as not conforming to sterility requirements. In some instances, such trends can appear to be more indicative of laboratory error as a possible source of a sterility test failure. Sterile Products A good error record can help eliminate a lab as a J.

However, theconverse is not true. Sectionduction problem. Accordingly, all sterility positives should Monitoring of Production Area EnvironmentOf particular importance is trend analysis of microorgan- All drug product production and control records, includ-isms in the critical and immediately adjacent area. Trends ing those for packaging and labeling, shall be reviewedare an important tool in investigating the product as the and approved by the quality control unit to determinepossible source of a sterility failure.

Consideration of envi- compliance with all established, approved written proce-ronmental microbial loads should not be limited to results dures before a batch is released or distributed.

Any unex-of monitoring the production environment for the lot, day, plained discrepancy including a percentage of theoreticalor shift associated with the suspect lot. It is therefore important to look at both short- whether or not the batch has already been distributed.

Theand long-term trend analysis. A writ-Daily personnel monitoring data and associated trends ten record of the investigation shall be made and shallshould be reviewed and can in some cases strongly indi- include the conclusions and follow-up. The adequacy of personnelpractices and training should also be considered. Maintaining process and environmental control is a daily necessity for an aseptic processing operation.

Product Presterilization Bioburden requirement for review of all batch records and data forTrends in product bioburden should be reviewed counts conformance with written procedures, operating param-and identity. All in-processf. Production Record Review data must be included with the batch record documenta-Complete batch and production control records should be tion per Section Review of environmental mon-reviewed to detect any signs of failures or anomalies that itoring data as well as other data relating to the accept-could have a bearing on product sterility.

For example, the ability of output from support systems e. While interventions or stoppages are normally recorded in the batch record, the manner of documentingg. Manufacturing History these occurrences varies. Past mented in batch records with the associated time anddeviations, problems, or changes e. Sterility failures can be attributed to atypical or extensive interventions that have occurred as a response to an undesirable event during the aseptic process. Inspection of Sterile Product Manufacturing Facilities 25procedures describing the need for line clearances in the manufacturing.

These studies should incorporate all prod-event of certain interventions, such as machine adjustments uct manipulations, additions, and procedures involvingand any repairs, should be established. Such interventions exposure of product contact surfaces to the environment.

However, process sim-able exposure time should, where appropriate, result in a ulations do not need to mimic total manufacturing time iflocal or full line clearance. Any disruption in power supply, the manipulations that occur during manufacturing arehowever momentary, during aseptic processing is a manu- adequately represented. It is also important that process simulations incorporate storage of product or transport to other manufacturing IV. There is a point in the process throughout the process.

Where possible, closed systemsafter which a product can no longer be rendered sterile by should be used during production of this type of products. When a sterility testing are not available before the product isproduct is processed aseptically from early steps, the prod- administered, additional controls and testing should beuct and all components or other additions are rendered considered.

For example, additional sterility tests can besterile prior to entering the manufacturing process. It is performed at intermediate stages of manufacture, espe-critical that all transfers, transports, and storage stages be cially after the last manipulation of the product prior tocarefully controlled at each step of the process to maintain administration.

Other tests that may indicate microbialsterility of the product. The environment ofthe room surrounding the Class environment should An emerging aseptic processing technology uses isolationbe Class 10, or better. Microbiological and particulate systems to minimize the extent of personnel involvementmonitoring should be performed during operations. A well-designed positive pres-end of operations but prior to cleaning.

Personnel moni- sure barrier isolator, supported by adequate procedures fortoring should be performed in association with operations. However, users should not adopt a false senseinterventions that could impact on the sterility of the prod- of security with these systems.

Manufacturers should beuct during manufacturing. The process simulation, from also aware of the need to establish new proceduresearly process steps, should demonstrate that controls over addressing issues unique to these systems. Sterile ProductsA. Pressure Differential1. General Isolators that include an open exit portal represent a poten- tial compromise in achieving complete physical separationIsolator systems have a number of special maintenance from the external environment.

A positive air pressurerequirements. The rounding environment have largely ranged from ca. Air balance between the isolator and other directparts before they break down or degrade. Glove Integrity The positive pressure differential should be coupled with appropriate protection at the product egress point s A faulty glove or sleeve gauntlet assembly represents a in order to overcome the potential for ingress of any air-route of contamination and a critical breach of isolator borne particles from the external environment by induc-integrity.

The choice of durable glove materials coupled tion. Local Class protection ataddressed. With every use, gloves should be visually eval- an opening can provide a further barrier to induction ofuated for any macroscopic physical defect.

Mechanical outside air into the isolator. Thisattentive preventative maintenance program is necessary 4. When such a breach is discov- The interior of the isolator should, at minimum, meetered, the operation should be terminated. Because of the Class standards. A Class 10, or Class , backgrounda second pair of thin gloves. The area surrounding the isolator shouldB. In most sound designs, supplies into and out of the isolator.

Air-handling systems should 1. Multiple material transfers are generally made during the2. Materials of Construction processing of a batch. Such provisions, if well designed, help ensure thatcleaning and sterilization.

For example, rigid wall con- microbiological ingress does not result from the introduc-struction incorporating stainless steel and glass materials tion of supplies. Properly operated RTPs rapid transferis widely used. Inspection of Sterile Product Manufacturing Facilities 27kept to a minimum because the risk of ingress of contam- 3. Frequencyinants increases with each successive material transfer. If an isolator is to be used for multiple daysviolet or a design that would compromise isolation by between decontamination cycles, the frequency adoptedallowing ingress of air from the surrounding room.

This frequency, established during validation studies,in the area of such a port should be implemented. Discharge of the isolator environment. Breaches of integrity should be investigated and anyshould be supplied and monitored on a continuous basis product that may have been impacted by the breachat this location to ensure that isolation is maintained.

Surface Exposure To ensure sterility of product contact surfaces from the start of each operation, the entire path of the sterile liquidWritten procedures for decontamination of the isolator stream should be sterilized. In addition, loose materials orshould be established. The decontamination process equipment to be used within the isolator should be chosenshould provide full exposure of all isolator surfaces to the based on their ability to withstand steam sterilization orchemical agent.

For example, to facilitate contact with the equivalent method. Decontamination can be accomplished by a ological quality of air, surfaces, and gloves or half-suits number of vaporized agents, although these agents possess as well as particulate levels within the isolator. Air qualitylimited capability to penetrate obstructed or covered sur- should be monitored periodically during each shift. As anfaces. Process development and validation studies should example, the exit port should be monitored for particulatesinclude a thorough determination of cycle capability.

The to detect any unusual results. Cycles should be developed with an appro- tion should not be overlooked. For most gloves for aseptic manipulations and handling of compo-production applications, demonstration of a six-log reduc- nent transfers into and out of the isolator. Contaminatedtion of the challenge BI is recommended.

The uniform gloves can lead to product nonsterility. Chemical indicators may also be useful as a qual- ing surface sterilization. Meticulous aseptic techniqueitative tool to show that the decontaminating agent reached standards must be observed Section Sterile Products VI. Furthermore, designs separating thecontinuous operation.

This section discusses some of the critical ing contamination. In addition to suitable design, an adequate preventa-A.

For example, because of its potential to contaminate the sterileA BFS machine operates by 1 heating a plastic polymer drug product, the integrity of the boiling system e.

In most operations, However, a properly functioning process is necessary tothe three steps that pose greatest potential for exposure to realize these advantages.Retesting for Sterility 2. The separation of of my graduate students and colleagues for their help. Particle Size Reduction and Separation Like this book? Personnel Practices J. The following list includes some for in this guidance e.

Although it is likely that some of the require- tion requirement, and the route of administration, mainly ments and recommendations made here might change, it topical. General 2. Preface to the Volume The semisolid drugs category is comprised of ointments.