Encyclopedia of Pharmaceutical Technology, Third Edition. L. Aguilar Yerenas. Volume 1 Volume 2 (Continued) 21 CFR Part 11 Revisited / 1 Drug Delivery. Encyclopedia of Pharmaceutical Technology, Third mtn-i.info - Ebook download as PDF File .pdf), Text File .txt) or read book online. Encyclopedia of. PHARMACEUTICAL. TECHNOLOGY. Third Edition. VOLUME 1. New York London edited by. James Swarbrick.
|Language:||English, Spanish, Dutch|
|Genre:||Science & Research|
|Distribution:||Free* [*Registration needed]|
Encyclopedia of. PHARMACEUTICAL. TECHNOLOGY. Third Edition. VOLUME 3 edited by. James Swarbrick. PharmaceuTech, Inc. Pinehurst, North Carolinia. Third Edition of use: mtn-i.info mtn-i.info . Encyclopedia of Pharmaceutical Technology DOI: /E-EPT- . By the third law of Newton, for every force there is a. Encyclopedia of PHARMACEUTICAL Third Edition Volume 1 21 CFR Part 11 this, the third edition, of the Encyclopedia of Pharmaceutical Technology. ( mtn-i.info cder/guidance/mtn-i.info): Class 1: High Solubility High.
What are excipients doing in medicines? The best new therapeutic entity in the world is of little value without an appropriate delivery system. Pharmaceutical excipients are substances that are included in a pharmaceutical dosage form not for their direct therapeutic action, but to aid the manufacturing process, to protect, support or enhance stability, or for bioavailability or patient acceptability.
They may also assist in product identification and enhance the overall safety or function of the product during storage or use. Many excipients have more than one use, which can be an advantage since it reduces the number of excipients needed and minimises the risk of interactions between them. Tablets are the most widely used dosage form.
Their manufacture can be a complex process and considerable ingenuity and formulation expertise are required to produce a product that will be stable during storage, transport and handling, yet will release its active pharmaceutical ingredient as required once ingested. Griffin Marketing of Pharmaceuticals Mickey C. Valinski Manufacture of Pharmaceuticals John C. Ronald P. Graham Nairn Greenberg Atkins Metered-Dose Inhalers: Pressurized Systems Gerald W.
Hickey 1 Moisture in Pharmaceutical Products R. Pramod K. Burgess and Anthony J. Eccleston Microencapsulation Joseph A. Halls Microemulsions Gillian M. Nonpressurized Systems Paul J. Kowalsky and Alan F. Gibson and H. Trends and Perspectives Frans W. Asbury Merkus and J. Turco Parenterals: Small Volume Michael J. Williams and Brian W.
Groves Partition Coefficients Eric J. Franz and Paul A. Wearley and Ajay K. Banga Percutaneous Absorption Thomas J. Brownlee Parenterals: Large Volume Salvatore J. Lawrence D. David Woolfson Polymers: Medicinal and Pharmaceutical Julian H. Grady 81 Photodecomposition of Drugs John V. Castle and Suzanne F. Gary W. Lewis Polarography and Voltammetry A. Robert D. Lima 29 Pharmacopeial Standards: Ralph B. Artiges 53 Pharmacopeial Standards: United States Pharmacopeia Jerome A. Franz Plant Products as Drugs D.
Halperin and Lee T. Braybook Polymorphism: James D. Liebe 1 Pharmacokinetics and Pharmacodynamics John J. William J. Hodges and Stephen P. Richard Mitchell. Jie Du.
Judi Moss. Rajagopalan Raghavan. Denyer 21 Prodrugs Lona L. Sheppard 1 Preservative Testing Norman A. Yarbrough Nak-Seo Kim.
Shah and James G. Bloomfield and Fiona C. Kenimer 71 Project Management Jerome J. Schulman and Phillip M. Bandelin and Bhogi B. Li 87 Sonophoresis: Stephen M. Fix and J. Sheth 31 Sieving of Pharmaceuticals John W. Currie and Richard W.
Daniel Blankschtein. Michael Newton Whicker 1 Semisolid Preparations Fred J. Augsburger and Mark J. Imre M. Chris Kiesnowski.
Zellhofer Tablet Testing James I. Joseph Unit Processes in Pharmacy: Fundamentals David Ganderton and Anthony J. Meltzer Sarkar and William H. Machine Theory. Patani and Yie W. Bogda Targeting of Drugs to the Gut I. Chien Ultrasonic Nebulizers Orla N. Davis Transdermal Drug Delivery Devices: System Design and Composition George A. Wilding and S. Myrdal and Samuel H. McCallion and Kevin M. Barbara Perry. Rhodes Index to Volume 19 Cocchetto and Sherman N.
Debra Barnes. Morisseau and Christopher T. Peters and Marghi R. Rowe and Ronald J. Ron J. The filling mandrels are comprised of a set of filling tips which are held within a protective air shower. It is then extruded through a die-and-pin set forming an open-ended tube of molten polymer known as a parison. The technology has been developed to an extent that today BFS systems are used to aseptically produce sterile pharmaceutical products such as respiratory solutions.
The parison is held in position by a clamp. The molded plastic is severed from the continuously extruding parison by a hot knife. The mandrels return to the protective air shower. This differs from conventional aseptic pro- cessing where container formation. Because of the level of automation of the entire process. Molding is facilitated by vacuum slots in the mold. A mold set consisting of two halves then moves over to the parison and closes around it.
The parison is supported by sterile air parison support air which is fed into its center through a sterilizing-grade air filter with oil- free compressed air.
When the molds are beneath the air shower. It is therefore possible to achieve very high levels of sterility confidence with a properly configured BFS machine designed to fill aseptically. Polymer granules are continuously fed to a machine hopper through an adiabatic screw extruder. The BFS technology is an advanced aseptic processing technique which allows plastic containers to be formed by means of molded extruded polymer granules. Total particle levels should meet the required specifications and be measured.
Microbi- ological monitoring for viable contaminants should be carried out to coincide with routine manufacture at normal levels of dynamic activity. The most recent BFS machines are also capable of operating with significantly lower particle levels.
A typical monitoring regime within the clean room would include quantitative air and surface monitoring. Alert and action levels should be clearly defined based upon both operational data and published recommendations.
The pathway is sterilized in place prior to receiving product. Within the European forum it is required that the clean room garments be worn to enter the class M5. The mold then opens and the filled containers surrounded by excess polymer are released. The localized filling environment or air shower is of a higher classification.
Recommended limits for viable contaminants not specific to BFS processes in clean rooms are quoted in various guidelines. There is usually more than one stage of sterile filtration required on the product pathway. Liquid product is fed to the BFS machine from a holding tank or vessel. Levels of viable contamination are. As with traditional aseptic filling. The BFS technology has the advantage of being able to operate without the continuous presence of personnel within the clean area.
Annex 1. Ex- cess plastic is removed typically on line by means of a mold-specific cropping tool. Semiquantitative air monitoring by the use of settle plates can also be useful in pro- ducing data associated with a longer period of time in operation up to 4 hr exposure.
A routine microbiological environmental monitoring program should be estab- lished and documented based on historical and operational data to demonstrate con- tinued compliance with specifications and to monitor trends. Filling Environment Aseptic BFS machines are housed within classified clean areas of a minimum speci- fication of class M5. The entire cycle takes only a few seconds. Levels of the tracer gas were measured within subsequently filled BFS units.
In both cases. Routes of air-borne contamination into BFS containers have been investigated during a study using sulfur hexafluoride SF 6 tracer gas . During this shuttling period. The study concluded that the container was effectively protected by the localized air shower. The air used to form the parison parison support air is typically sterile filtered air.
During this experiment. Surface samples. Consideration should also be given to monitoring the localized filling zone air shower. Although not necessarily representative of deposition of microbial contaminants. If this is not the case. It may also be feasible to install a remote means of obtaining samples during operation. It has been demonstrated  during a simple practical experiment that broth-filled units totalling over Classification Air.
During a more controlled study carried out within an environment artificially con- taminated with high levels of individual nebulized spores of Bacillus subtilis . Although access to this area is prohibited and extremely dangerous during operation. The environment was contaminated by means of high levels of personnel activity in order to generate contaminants in keeping with those generated under normal conditions albeit at grossly elevated levels.
The bioburden of polymer granules can be tested to establish base-line data. Extensive process simulation broth fill results for BFS effectively demonstrate that high levels of sterility confidence can be obtained with a properly configured and validated machine.
Initial machine adjustments are necessary for integral and visually acceptable units of the correct fill volume to be consistently produced. The BFS container is produced from high-grade virgin polymer granules.
This sterilized bulk solution can be used to feed the filling machine without escalation of microbial levels.
In order to facilitate this with respect to maintaining a low bioburden throughout all stages of liquid processing. It is dependent upon the manufactur- ing process. Virgin polymer granules. Considerable machine downtime is required with BFS technology associated with activities such as clean in place CIP and steam in place SIP to prepare a machine for manufacture.
Raw materials should be of a high quality and tested for microbial contamination. Studies have been carried out to investigate the lethality of the extrusion process with respect to container sterilization. Contamination from Product Components As with traditional aseptic filling. Further stages of ster- ile filtration are required on the filling machine closer to the point of fill.
Water used for product manufacture should be of low bioburden and high purity preferably water- for-injection quality. It therefore can be advantageous to fill larger product batches once this is achieved. A program of bioburden testing for each product batch at various stages of manu- facture should be established and documented.
The control of environmental contamination within the clean room is therefore important. The maximum life of the bulk solution in a nonsterile environment generally within a mixing tank should be limited to prevent increase in bioburden beyond an acceptable level.
A facility for sampling products during the course of the filling stage prior to further filtration can be incorporated. Coolant systems are an integral part of container formation and serve to cool the molds and. Coolant systems are prone to microbi- ological contamination and should be routinely treated to keep the bioburden under control.
They should be regularly sampled and tested for bioburden to ensure continu- ous compliance to a predefined specification. Maintenance activities should ensure that moving parts are sufficiently but not overly lubricated.
BFS machines must be properly maintained. BFS machines are complex and some operator activity is required from time to time during normal manufacture. Regular seal changes with reconciliation of new and old seals should be included. Activities such as parison and fill volume adjustments are part of the normal operation of the machinery and are permitted. As with all machinery. A documented preven- tative maintenance program should be in place.
There must be clearly documented rules to clarify which activities are prohibited during batch manufacture and which are permitted. Operator intervention during machine operation is limited due to the na- ture of the technology. Moving parts should be inspected at regular intervals to prevent abrasion and to check for wear and tear.
Interventions should be categorized according to their potential for affecting the product being manufactured. Blow-Fill-Seal Aseptic Processing 5 Equipment In order to produce sterile pharmaceutical products with a high degree of sterility confidence. Validation The BFS machinery and associated equipment for aseptic manufacture should be constructed in such a way that the product pathways are of hygienic design with hygienic valves and minimal joints to facilitate cleaning and sterilizing in place.
Abrasion between moving parts. For example. There should be a proceduralized means of documenting these activities. An accurate engineering line drawing of the system to aid identification of suitable test locations and document test locations selected should be available.
Validation of SIP cycles should be carried out to demonstrate that consistent sterilization temperatures are achieved throughout the equipment to prove that the system can be effectively sterilized.
Means of measuring CIP efficacy include analysis of swabs taken directly from product contact machine parts and analysis of rinse waters. There is no appropriate defined sterility confidence level which can be translated directly into acceptance criteria for broth fill contamination for BFS processes.
CIP is necessary for all equip- ment in contact with the product.
The SIP cycles are routinely measured by thermocouples located in fixed positions along the product pathway. Validation should also identify suitable positions for routine use. This should be reflected by broth fill results and acceptance criteria for this advanced technology. Qualification of Aseptic Filling The standard.
When establishing areas for swabbing. This would typically include a bulk mixing tank. Units of liquid microbiological growth media usually a full-strength general purpose medium such as Tryptone Soy Broth are filled and incubated. The SIP validation is generally carried out with the help of additional thermocouples and should include the use of biological indicators appropriate for moist heat sterilization.
In this way. Test locations should include areas which may be prone to air or condensate entrapment. The CIP validation should be carried out to establish routine CIP prac- tices which clean the manufacturing equipment in such a way that the products manu- factured would be free of contamination and that safety.
Following an appropriate incubation period. During the course of a broth fill. The machine should be cleaned and sterilized by the usual procedures. It can also be useful to retain and incubate reject units filled during the course of a broth fill batch again. Frequency and size of broth fills must be clearly defined.
Tables have been published to this effect . The operator activity required at the start of a product batch is arguably more intrusive than at any other stage of manufacture. Such interventions should be planned and documented for each batch.
A deviation from routine processes should only be in the direction of presenting a higher rather than a lower challenge to the process. The size of fill is usually based upon the statistical probability of detecting an acceptably low incidence of microbial contamination. For a new facility. It is important that environmental monitoring data are obtained during the course of broth fill batches to demonstrate a normal level of environmental contamination.
The validity of broth fills carried out in an environment of consistently lower contami- nation levels than those obtained during routine batch manufacture could be ques- tioned. Batch manufacture.
Such units should be sepa- rated from the subsequent units meeting the acceptance criteria and labelled accord- ingly. Although such units would be rejected during normal production. For high speed BFS machines used for filling routine product batches in excess of Broth fills should be carried out under conditions that are representative of those during normal operation.
Product units routinely produced at the start of a batch are usually discarded because of fill volume. Blow-Fill-Seal Aseptic Processing 7 Broth fills should be a major part of the operational qualification of a new BFS machine to demonstrate aseptic processing capability prior to product manufacture typically three successful consecutive broth fills are required and should be carried out at defined intervals thereafter.
Due to the level of automation of BFS technology. This is commonly achieved by agitation or inversion of the units before or during the incubation period.
In addition to the data in Table 2. A recent study of the lethality of the extrusion process chal-. It is clearly impractical to produce a very high number of broth filled units on a routine basis. This procedure should also be carried out if modi- fications to a filling machine have been made which may have an effect on process capability e. In the absence of a definite cause.
The internal surfaces of broth filled units should be fully wetted to ensure capture of any contaminants within the broth. This should be routinely demonstrated by including positive control units inoculated with a low level of com- pendial microorganisms. Some of the media fills carried out were full production batch volumes with hun- dreds of thousands of units filled in a single batch.
Additional testing is desirable to demonstrate that the incu- bation time and temperature selected promote the growth of isolates obtained from machine operating environments. During broth fills of standard size. Given the high performance demonstrated during media fills.
These results. Incubation time and temperature should be adjusted so that macroscopic microbial growth of a wide range of common isolates will be detected.
Even very slight misalignment may potentially lead to the production of units with very slight leaks which may be difficult to detect by routine methods. In order to minimize the number of leaking units. Routine bioburden testing of virgin pharmaceutical-grade polymer granules tends to give very low or zero counts per gram of polymer tested. The integrity of the container can be tested effectively by a bacterial challenge. The experiment demonstrated a relationship between polymer contamination and product contamina- tion which was dependent upon both the level of contamination in the polymer and the resistance of the contaminant in terms of D value to dry heat sterilization.
The same strain was the organism of choice for biological indicators used in dry heat sterilization processes. The spores of the test organism Bacillus subtilis var. This is further endorsed by routine broth-fill data. Correct molding is therefore of key importance and can usually be simply checked by careful and experienced visual examination of units.
The study also demonstrated spore inactivation on granules with strong evidence of lethal- ity associated with the extrusion process. Spore contamination of units was observed with batches of polymer inoculated with high spore levels.
Filters used should be. This method is extremely sensitive. The study detailed was car- ried out using a BFS machine adjusted to extrude at the lower end of the operating temperature range for extrusion. Filtration Hydrophilic and hydrophobic sterilizing-grade filters are used throughout the BFS process for the sterilization of product and air. An absence of growth shows an integral unit and closure.
Thus there is evidence that the extrusion process renders the contaminants unavailable. The BFS containers are closed within the automated process by the head mold set forming around the top of the severed section of parison following filling. Using this method.
The integrity of the container and closure is generally tested by a manual or automated method of leak detection performed outside of the filling environment following re- moval of excess plastic deflashing from the filled product units. Units are then removed. BFS News.
PDA J.. Summary Aseptic pharmaceutical BFS technology for the manufacture of sterile liquid products has demonstrated high levels of sterility assurance when correctly operated and con- figured. References 1. This means. A case study. Qualification of hydrophilic filters is also necessary to demonstrate that the specific product type in conjunction with a bacterial challenge does not affect the filter efficacy.. BFS Operators Association. PDA J. The technology is continually improving as more expertise is developed..
Hydrophobic filters do not come directly into contact with the product.
Validation of filters by means of bacterial retention tests requires special equipment and is often arranged between the filter manufacturer and the BFS oper- ator. An exploratory study. How- ever.. Newly evolving dosage forms and therapeutic approaches suggest that compounding of pharmaceuticals and related products specifically for individual patients will be- come even more common in pharmacy practice.
Pharmacy is the art or practice of preparing and preserving drugs. Pharmacy activities to individualize patient therapy include compounding and clinical functions. Most compounding pharma- cists appear to be very interested and excited about their practices. All pharmacists should understand the options presented by compounding. Even today. Pharma- ceutical compounding is an area that is rapidly growing and providing needed prod- ucts and services to patients and healthcare practitioners.
No longer is pharmacy simply community pharmacy or hospital pharmacy. Compounding is a professional prerogative that pharmacists have performed since the beginning of their profession. In fact. Compounding has always been a basic part of pharmacy practice. The demonstrated expertise. Contemporary Introduction Pharmacists are unique professionals. Pharmaceutical compounding is dramatically increasing due to the impact of home health care.
It is a diverse profes- sion and offers many opportunities for those willing to look around. Pharmacists possess knowledge and skills that are unique and not duplicated by any other profession. Pharmacy is a complex mixture of different practices and practice sites.
This is because of the reputation of pharmacists being available in the local community to interact with patients. What area of pharmacy practice has the opportunity of using the scientific education and training as much as pharmacists involved in individualizing patient care through extemporaneous compounding?
The pharmaceutical sciences. Compounding also includes the preparation of drugs and devices in anticipation of prescrip- tion drug orders based on routine. It has been stated  that: Recent history leads one to question whether we in the profession. The use of clinical skills and physician— patient interaction have been identified in previous studies as intrinsic factors that enhance a pharmacists job satisfaction [4—7]. It may mean the preparation of oral liquids. Compounding may hold different meanings to different pharmacists.
Contemporary A pharmacy compounder may be defined as a pharmacist who actively promotes and provides prescription compounding services for the express purpose of attracting this type of prescription to his or her practice. Definition of Compounding Compounding has been defined by the National Association of Boards of Pharmacy  as follows: Compounding means the preparation.
The pharmaceutical sciences are what make us unique. They provide us the special value that we bring to the bedside.
In addition. No other health professional is capable of bringing to the pharmacotherapeutic decision-making table such concepts as pH. Pharmaceutical compounding requires training in mathematics. One of the responsibilities of a com- pounder requires that the pharmacist become actively engaged in the clinical assess- ment of a patient to assist the prescriber in determining the customized patient- specific formula to be extemporaneously compounded. Contemporary 13 dosage form into another.
Due to the unique nature of compounded medications. The latter situation generally encourages a team approach to health improvement.
Pharmacists have an opportunity to extend their activities in patient care as the emphasis continues to shift from inpatient care to ambulatory care. A general char- acteristic of an ambulatory patient is that he or she is generally responsible for ob- taining the required medication. Since when does the availability. Little financial consideration is given to counsel- ing. The tasks of pharmacists in ambulatory care patients can include. Ambulatory care offers a variety of opportunities for individualiz- ing patient care through pharmaceutical compounding.
Institutional Pharmacy Compounding The ever-present responsibility of the health care industry is to provide the best avail- able care for the patient. The term actually can also be applied to homecare patients and even institutionalized patients that are mobile. From the above discussion of the activities of an ambulatory-care pharmacist. Most reimbursement for ambulatory patients originates in the dispensing or compounding process. One of the effective means by which institutions.
Individualized dosage forms.
Institutional pharmacists have always been actively involved in compounding. The preparation of pediatric dosage forms has also been an area of extensive activity in some institu- tions.
As physicians become aware of the skill. Veterinary Compounding The first symposium on veterinary compounding in September  offered a significant forum for discussion by experts and provided a pivotal point in the history of veterinary compounding.
Improving outcomes will assist the medical staff in allowing them to spend their time dealing with new problems as hospital pharmacy meets the challenge of past problems. This requires cooperation on the part of the institutional administration.
As the institutional pharmacy staff demonstrates expertise and problem-solving skills. The interest of the Food and Drug Administration FDA in compounding by and for veterinarians dates back to the early s. Nursing and pharmacy will have an enhanced opportunity to interact and use the skills they have developed.
Contemporary a conducive environment. In the consideration of meeting patient-specific needs. Pharmaceutical care and pharmaceutical com- pounding can provide cost savings to the institution while providing needed options to the physician through problem-solving approaches and stimulating the institutional pharmacist through new challenges that allow the expression of both skills and art.
The meeting was important because it assembled an impressive group of experts on veterinary compounding. Members of the institutional staff are familiar with the current literature and are generally aware of innovative thought and practices by their peers. Related Information. Email or Customer ID. Forgot password? Old Password. New Password. Your password has been changed. Returning user. Request Username Can't sign in?