Aseptic Processing: Validation

Abstract

Aseptic processing is a widely used methodology in the health care industry for the preparation of sterile materials. The term aseptic processing as it is applied in the pharmaceutical industry refers to the assembly of sterilized components and product in a specialized clean environment. The clean environment may be a conventional human scale classified clean rooms or an environment engineered to further reduce the likelihood of contamination by reducing (or as much as is possible eliminating) direct human contact with the product and components being assembled “aseptically.” The idea of sterile products manufactured aseptically is inherently contradictory, a demonstrably sterile product cannot be produced aseptically using even the most advanced technology available today. Nevertheless, on any given day millions of putatively sterile dosage form units are produced using aseptic techniques that in the literal sense are inadequate to achieve sterility. A sterile product is one that is free from all living organisms, whether in a vegetative or spore state. This is an absolute condition, something cannot be partially or nearly sterile, the presence of a single viable organism represents a failure of the product, and the systems (environment, equipment, and procedures) used to produce it. Asepsis, that state in which all aseptically filled sterile products are manufactured, cannot be established as “sterile.” Asepsis is commonly defined as a condition in which living pathogenic organisms are absent.

Putting aside the classical definitions, one must consider the real difficulty in establishing an aseptic environment, let alone a sterile one. The practitioner is left with a insurmountable task, to somehow create an environment free of any organisms, but also one (with the exception of isolators) in which personnel must be present to perform critical functions. The problem is further compounded if it recalled that personnel are considered the single greatest source of microbial contamination in aseptic processing. Recent experiments have shown that personnel clothed in new, sterile clean room garments slough viable contamination at a rate of roughly one viable particulate to 10,000 non-viable particles. During slow deliberate movements with the best possible clothing, operators will slough particulate and viable organisms. Therefore, the probability of human borne microbial contamination being released in the conventional clean room is one over the course of any reasonably long operational shift. With this fact in mind, how then is one to accomplish a truly sterile or even aseptic environment? Especially when we must consider that many organisms that are normally non-pathogenic, can under certain circumstances become opportunistically pathogenic. Among those circumstances are a debilitated condition of general health in the patient, or, as is increasingly common, immunological insufficiency due to age or pre-existing condition.

Other than the obvious considerations of proper facility design, sterilization validation, and sanitization procedures (all of which are discussed elsewhere in this encyclopedia), the focus of attention must be on the personnel and the activities which they must perform. These actions are broadly termed, aseptic technique, and like any other human activity they can be accomplished in a variety of ways. In order to better understand aseptic technique, some general guidance and examples of good and bad technique can be used to delineate what should and should not be permitted.

The fundamental concept behind every aseptic processing activity is that non-sterile objects must never touch sterile objects. This is often accomplished by the establishment of a “sterile field” in which the core activities are performed. All of the surfaces of the gowned human operator must be always considered non-sterile. Non-sterile objects including the operators hands must never be placed between the source of the air and a sterile object. The operators' hands and arms must always be kept at a level beneath that of open product containers. Sterile components should under no circumstances be touched directly with gloved hands, a sterilized tool should always used for this purpose. Since gloved hands and arms will enter the sterile field they must never touch walls, floors, doors, etc. Strenuous lifting and moving of tanks, trolleys, etc. must not be done by operators assigned to work within or near the sterile field, because the more strenuous the activity the higher the level of particle generation, and at least some of the particulate released by the operator will surely by viable microorganisms.

Some of the techniques to avoid include: reaching over exposed sterile objects to make adjustments beyond them; correcting a stopper feed problem with a gloved hand; touching face, eye shield, or any other non-sterile object with gloves; taking an air sample directly over open containers; continuously standing inside flexible partitions that mark the boundary of the sterile field; breaking up clumps of components with gloved hands. Each of these actions exposes the sterile objects to undue risk of contamination from the personnel. Certainly there are more ways to contaminate the “sterile field” than we can imagine. For this reason, the procedures used in and around the “sterile field” must be carefully defined and followed closely by all personnel. These procedures should follow the general principles outlined above and are evaluated in a media fill simulation and performed in an identical fashion during aseptic processing. It is beneficial to define in writing how each procedure is to be performed and train the operators in these exact procedures. View Section: View Article (PDF)

Validation of Active Pharmaceutical Ingredients

Validation of Active Pharmaceutical Ingredients Book Description

Much has happened in the area of bulk pharmaceutical good manufacturing practice (GMP) and validation since the first publication of Validation of Active Pharmaceutical Ingredients. Revised, updated, and expanded, this second edition includes new chapters addressing postapproval changes, technology transfer, international cGMP guidelines/FDA guidance progress, and facility inspection issues. The basic philosophy and principles of GMP and validation have not changed, but new terminology had been introduced, and old terminology had been better defined, improving the understanding of related concepts and principles. The book gives you a working knowledge of the regulatory process that will facilitate your organization's compliance with regulations.

Robin Goldstein has contributed to Validation of Active Pharmaceutical Ingredients as an author. Niles Elliot Goldstein is the founding rabbi of The New Shul in Greenwich Village, New York. He lectures widely on Jewish mysticism and spirituality and has taught at New York University and the Hebrew Union College-Jewish Institute of Religion. Goldstein is the national Jewish chaplain for the Federal Law Enforcement Officers Association and was the voice behind "Ask the Rabbi" on the Microsoft Network. His essays and poetry have appeared in "Newsweek, the "Los Angeles Times, and many other publications, and he is the author or editor of five previous books, including God at the Edge: Searchi

Publisher: Informa Healthcare

Author: Santoro, Robin Goldstein, Berry R Berry

Edition Number: 2

Language: English

ISBN:

1574911198

EAN:

9781574911190

No. of Pages: 588

Publish Date: 2008-01-31

A Practical Guide to Microbial Limit Methodologies

A Practical Guide to Microbial Limit Methodologies
In recent years, the field of pharmaceutical microbiology has experienced numerous technological advances, accompanied by the publication of new and harmonized compendial methods. It is therefore imperative for those who are responsible for monitoring the microbial quality of pharmaceutical/biopharmaceutical products to keep abreast of the latest changes. Microbial Limit and Bioburden Tests: Validation Approaches and Global Requirements guides readers through the various microbiological methods listed in the compendia with easy-to-follow diagrams and approaches to validations of such test methodologies.
Includes New and Updated Material
Now in its second edition, this work is the culmination of research and discussions with technical experts, as well as USP and FDA representatives on various topics of interest to the pharmaceutical microbiologist and those responsible for the microbial quality of products, materials, equipment, and manufacturing facilities. New in this edition is an entire chapter dedicated to the topic of biofilms and their impact on pharmaceutical and biopharmaceutical operations. The subject of rapid methods in microbiology has been expanded and includes a discussion on the validation of alternative microbiological methods and a case studyon microbial identification in support of a product contamination investigation.
Substantially updated and revised, this book assists readers in understanding the fundamental issues associated with pharmaceutical microbiology and provides them with tools to create effective microbial contamination control and microbial testing programs for the areas under their responsibility.

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Validating Chromatographic Methods: A Practical Guide

Validating Chromatographic Methods brings order and Current Good Manufacturing Practices to the often chaotic process of chromatographic method validation. It provides readers with both the practical information and the tools necessary to successfully set up a new validation system or upgrade a current system to fully comply with government safety and quality regulations. The net results are validated and transferable analytical methods that will serve for extended periods of time with minimal or no complications.

This guide focuses on high-performance liquid chromatographic methods validation; however, the concepts are generally applicable to the validation of other analytical techniques as well. Following an overview of analytical method validation and a discussion of its various components, the author dedicates a complete chapter to each step of validation:

• Method evaluation and further method development
• Final method development and trial method validation
• Formal method validation and report generation
• Formal data review and report issuance

Templates and examples for Methods Validation Standard Operating Procedures, Standard Test Methods, Methods Validation Protocols, and Methods Validation Reports are all provided. Moreover, the guide features detailed flowcharts and checklists that lead readers through every stage of method validation to ensure success.

For scientists and technicians new to method validation, this guide provides all the information and tools needed to develop a top-quality system. For those experienced with method validation, the guide helps to upgrade and improve existing systems.

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Method Validation in Pharmaceutical Analysis: A Guide to Best Practice

Hardcover: 418 pages
Publisher: Wiley-VCH (May 6, 2005) English ISBN-10: 3527312552 ISBN-13: 978-3527312559
File type : PDFFile
size : 2.9 MB
Book Description
Adopting a practical approach, the authors provide a detailed interpretation of the existing regulations (GMP, ICH), while also discussing the appropriate calculations, parameters and tests. The book thus allows readers to validate the analysis of pharmaceutical compounds while complying with both the regulations as well as the industry demands for robustness and cost effectiveness. Following an introduction to the basic parameters and tests in pharmaceutical validation, including specificity, linearity, range, precision, accuracy, detection and quantitation limits, the text focuses on a life-cycle approach to validation and the integration of validation into the whole analytical quality assurance system. The whole is rounded off with a look at future trends. With its first-hand knowledge of the industry as well as regulating bodies, this is an invaluable reference for analytical chemists, the pharmaceutical industry, pharmaceutists, QA officers, and public authorities.


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Document creation and execution

• Validation Master Plans
• User Requirements
• Functional Specifications
• Design Documents
• Factory Acceptance Tests
• Impact Assessments
• Installation Qualifications
• Operational Qualifications
• Controls / Automation Qualifications
• Computer Systems Validation
• Performance Qualifications
• Disaster Recovery Procedures
• SOP Development

Concept of Process Validation For Pharmaceutical Industry

Concept of validation
GMP-definition is the validation of "establishing documented evidence that establishes a high degree of certainty that a particular process will consistently a product that provides the previously established specifications and quality attributes are available."
Appropriate and complete documentation is recognized as crucial for the validation. Standard Operating Procedures (SOPs), production formulas, detailed documentation batch changeControl, experimental reporting systems, analytical documents, reports development, validation protocols and reports are an integral part of validation philosophy. The validation of the documentation provides a source of information for the ongoing operation of the plant and is a resource that is used in the subsequent process of development or modification activities.
All test activities will take a level of impact assessment to ensure that systems, services andProducts were determined directly affected by the test.
A revalidation program should be implemented on a permanent equipment on the revalidation requirements and change control.
Types of Validation
Prospective validation
Establishing documented evidence that a device / process or system to do what they do, on a pre-planned series of scientific investigations within the meaning of validation sets basedPlan.
Concurrent validation
Is used when an existing process can be shown to be in a state of control by use of tests on samples taken at strategic points in a process, and at the end of the process. All data are collected simultaneously with the implementation of the process, to demonstrate sufficient information to process reproducibility.
Retrospective Validation
Establishing documented evidence that a process does notwhat it purports to do, based on review and analysis of historical data.
Design Qualification (DQ)
The intent of the DQ is in the planning and commissioning process met with a number of mechanisms, including:
- Generation of User Requirement Specifications
- Verification of this type corresponding user requirement specifications.
- Supplier Evaluation / Audit
- Check the Challenge of the design by GMP audits
- Product Quality ImpactAssessment
- Specifying Validation documentation requirements of suppliers
- Agreements with the suppliers about the performance targets
- Factory Acceptance Test (FAT), Site Acceptance Test (SAT) and commissioning procedures
- Definition of construction and installation documentation) to assist with Installation Qualification (IQ.
Installation Qualification (IQ)
IQ is a proof that the equipment or system has been documented in developeddelivered and installed in accordance with design drawings, vendor recommendations and in-house requirements. Moreover, IQ, that a record of the main features of the equipment or system is installed, how available and ensure that they are supported by sufficient and appropriate documentation to implement satisfactory operation, maintenance and control of changes.
Operational Qualification (OQ)
OQ is documented proof that operates the facilityas provided in the above design, operation or approved acceptance range of equipment, as applicable. In cases where process steps are considered an appropriate placebo batch is used to demonstrate device functionality.
All new devices should be fully taken into service before the start of OQ to ensure that at least be sure to use the device, complete with all mechanical assembly and pre-qualification checks are that the device is fully functional and thatDocumentation is complete.
Performance Qualification (PQ)
The goal of PQ is documented proof that the equipment can always be achieved while producing the specifications for a longer period at a defined operating point, a product of the specified quality. The specification will make reference to process parameters, in-process and product specifications. PQ requires three product batches available for all acceptanceCriteria for in-process and product testing. For supply PQ requires the benefits of medium to fulfill all the data over a longer period of sampling.
The PQ documentation should be on standard manufacturing procedures and batch records and describe the methodology of sampling and testing to be.
What is Validated
General
All process steps, production equipment, systems and environment, directly relevant to the production ofsterile and non-sterile products must be formally confirmed.
All major packaging equipment and processes should be validated. This validation is less comprehensive.
All ancillary systems, which should have no direct effect on product quality to be qualified by a technical documentation on the extent of the system and how it works.
Facility
- Manufacturing Area Design.
- Personnel and material flow, etc.
Process Equipment andDesign
Process steps and equipment description. Ie dosing, formulation, packaging, washing equipment
and cleaning. etc
Utility Systems Design
Raw / steam cleaned, purified water, compressed air, air conditioning, vacuum, power, lighting, cooling water, wastewater, etc.
Computerized Systems Design
Information system, automated laboratory equipment, automated manufacturing equipment, electronic recordsetc
Cleaning validation (CV)
CV provides evidence documenting that a cleaning procedure for the reduction of effective pre-defined maximum allowable limits, all chemical and microbiological contamination by one piece of equipment or a production area for processing. The means for evaluating the effectiveness of cleaning includes cleaning and disinfecting surfaces, sampling and inspection of product residues, cleaning residues and bacteriaContamination.
The term CV is used to describe the analytical investigation of a cleaning or by bicycle. The validation protocol should be based on background documentation on the reasons for the "worst case" test, where it is proposed. It should also develop the criteria for acceptance, including chemical and microbiological specifications, limits of detection and the selection of sampling.
Method Validation (MV)
MVprovides documented evidence that the internally-developed test methods are accurate, robust, efficient, reproducible and repeatable. The validation protocol should be based on background documentation on the reasons for determining the method detection limit and sensitivity.
Computer Validation
Computer Validation is a proof to ensure systems are consistently documented in accordance with the predetermined specifications and quality functionAttributes throughout their lifecycle. Important aspects of this approach are) the validation of formal management design (through a specification process), system quality (through systematic review and testing, risk (through the identification and evaluation of new and critical functions) and lifecycle (through sustainable change Control).
If the equipment in embedded computer systems, the elements of the validation of computer controlled, can be carried out as part of the equipment IQ and OQProtocols.

Validation Findings in FDA Warning Letters 2008

The GMP news from 18 February 2009 comprised information on the FDA Warning Letters Report 2008, including the Top 5 deficiencies.

It did not cover deficiencies regarding validation (validation/qualification/calibration) though. This is due to the fact that the findings are listed according to the paragraphs in the 21 CFR 210/211, which does not contain a separate paragraph addressing (process) validation. For that reason the following information does provide an individual validation issues analysis:

In the 22 Warning Letters in the fiscal year 2008 issues regarding validation were criticised 15 times. Top of the list were deficiencies relative to process validation (9 Warning Letters). Five of the letters referred to deficiencies concerning solid dosage forms, 2 concerned semi-solid forms, one addressed radio pharmaceuticals, and one product classification remained unclear.

Two Warning Letters per subject covered issues like inappropriate validation of the sterilisation process, filter validation, "smoke studies" and cleaning validation the authority issued like

Exemplary findings for the issues mentioned above are:

Exclusion of validation batches without providing reasons within a retrospective validation
Missing sampling details in the validation plan
It seems like you did not understand the meaning of a cleaning validation
The cleaning validation master plan does not contain any "scientific rationale" for specific products, sampling locations and acceptance criteria
Swab surfaces are too small
Not all loading patterns were mapped in the validation of the sterilisation process
Inadequate Air Flow Pattern
Further deficiencies concerned issues like

An inadequate calibration of thermocouples
A Media Fill not representing a commercial process
Undocumented removal of filled vials within Media Fills
Conclusion: Although the subject validation is not specifically listed in the 21 CFR 210/211, it still is among the top deficiencies in the Warning Letters issued. Almost 70% of all letters contained one or several findings relative to this subject. 41% were related to process validation.

Validation of USP Methods

In the first supplement of the USP 32, the revised, general chapter <1225> - Validation of Compendial Methods - was published. This chapter describes the requisite performance characteristics that should be considered to prove the validation of a method in the case of its submission to the Pharmacopoeia.

It is striking that terms coming from ISO standards have also been incorporated, although the wording in pharmaceutical surroundings was until now oriented towards the ICH Guidelines, especially ICH Q2(R1).

This was also the topic of the publication entitled "Making Sense of Trueness, Precision, Accuracy, and Uncertainty" in the Pharmacopoeial Forum of May-June 2008. This article reviews the differences between the terms when used in ICH and ISO. It also states that the terms "trueness" and "uncertainty" do not even exist in the ICH and the USP. The conclusions drawn in this article are as follows: The terms should be clarified in the USP. These clarifications could easily be added to the General Chapters <1010> und <1225>. In the longer term, the USP encourages continued harmonisation of terminology among the involved parties (ISO, ICH, VIM - International Vocabulary of Metrology) and other interested parties.

In the revised chapter <1225> of the first supplement to USP 32, these terms have now been incorporated from ISO 5725-1 and ISO 3534-1.

And the term "reportable value", established from the OOS discussions in recent years, is now also incorporated in this USP chapter.

The requisite performance characteristics to be considered in validation of the types of methods in order to prove their suitability for the USP (accuracy, precision, specificity, detection limit, quantitation limit, linearity, range and ruggedness) remained unchanged.

And when is it necessary to revalidate? Revalidation may become necessary when a revised analytical method is submitted to the USP or when an established, general method is to be used for a new product or for a new starting material.

Pharmaceutical Master Validation Plan: The Ultimate Guide to FDA, GMP, and GLP Compliance.

Pharmaceutical Master Validation Plan: The Ultimate Guide to FDA, GMP, and GLP Compliance.
By Syed Imtiaz Haider

• Publisher: Informa HealthCare
• Number Of Pages: 208
• Publication Date: 2001-12-27
• ISBN-10 / ASIN: 1574443305
• ISBN-13 / EAN: 9781574443301
• Binding: Hardcover

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Product Description:

The Master Validation Plan provides a roadmap to management for on-time start-up of facility operations, and validation of existing facilities, in compliance with GMP requirements. The lack of a comprehensive Master Validation Plan and well-documented validation procedures is the main reason that new drug, medical device, medical equipment, and related product applications are rejected by the FDA. In fact, only about 2% of the applications submitted by foreign pharmaceutical companies are approved each year. This thorough guide provides the needed solutions and guidance for both foreign and U.S. companies to achieve FDA compliance and authorization to market their products in the United States. Pharmaceutical Master Validation Plan: The Ultimate Guide to FDA, GMP, and GLP Compliance will allow you to more easily achieve satisfactory inspections, new medical product approval, minimize non-conformance, reduce rework and rejected lots, and avoid recall lots by developing and managing a Master Validation Plan. The accompanying CD allows users to input the template plan into their computers and tailor it to incorporate additional regulatory requirements specific to individual companies worldwide and print the required documents. Together, the book and CD contain everything required to develop and execute a successful Master Validation Plan based on FDA guidelines for the pharmaceutical industry, and allows the templates to be extended to diagnostic products, medical device, medical equipment, and biotech industry products.

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http://www.filefactory.com/file/6b6111/n/1574443305_zip

Ion Spectrometry to Cut Cleaning Validation Time

Cleaning validation is a critical part of current Good Manufacturing Practice (cGMP), requiring manufacturers to spell out, and then verify, the procedures that they use to clean their equipment. After cleaning, operators typically use high pressure liquid chromatography (HPLC) to sample reference materials and determine whether cleaning procedures are up to snuff. HPLC may be effective, but it's also time-consuming, and facilities can be down for a day or two, at a cost of $1 million per day, while samples are collected and analyzed.

A new alternative to HPLC, ion mobility spectrometry (IMS), is attracting more attention, and offers the potential to shorten the turnaround time by quickly verifying equipment cleanliness. The market currently is led by Smith's Detection (Warren, N.J.), formed two years ago through the merger of Graseby Dynamics in the U.K., Barringer Instruments and Environmental Technologies Group.

Smith's came out with its first Ionscan spectrometer in the early 1990s. Military and security applications have driven the business. The equipment was widely used during the Gulf War, and has been a mainstay for airport security since the downing of Pan Am Flight 103. However, the company soon realized potential pharmaceutical applications, and established its life sciences division over two years ago---just before September 11, according to division vice president Robert Sandor, a Ph.D. chemist who had previously worked in the lab analytical equipment business.

The company faces competition next year, when GE Infrastructure Sensing (Leicester, U.K.) plans to roll out the first commercial products based on its ITMS (ion trace mobility spectrometry) trace-detection technology, which is now in beta testing. "We will be working closely with pharmaceutical manufacturers and cleaning validation experts to build appropriate libraries of fingerprints and assess overall performance," says marketing director Michael Hardcastle, based in Billerica, Mass.

Smith's claims that its Ionscan-LS, when used with a high-performance injection (HPI) system can reduce downtime by more than 75%. So far, drug manufacturers including Bristol Myers Squibb, Forest Laboratories and Glaxo Smith-Kline, have tested Smith's Ionscan and found that it can shorten cleaning validation time from days to hours, enabling significant reductions in downtime.

Ion spectrometry determines composition and concentrations by how quickly sample ions move through a gas subjected to an electric field---mass, charge, size and shape all help determine each ion's speed. Users say the technique can detect nanogram quantities of compounds, well within the ppm standards required by cGMP. Instead of the preparation and set-up needed for HPLC, which requires highly skilled technicians, Ionscan requires that 1 microliter of solution be placed on a PTFE disk, and then dried for one minute. Ionscan analysis is complete within 45-60 seconds, compared with up to 10 minutes for HPLC.

To detect compounds with high proton affinity such as amines or ketones, the device is typically run in positive mode, using nicotinamide as calibrant and reagent, according to Bristol Myers Squibb scientists, who used the technique to examine five drug formulations, and presented their findings at a recent meeting of the Eastern Analytical Society. For compounds with high electron affinity such as anhydrides, negative mode is used, with methyl salicylate as calibrant and chlorine as reagent.

Bristol Myers Squibb found that using Ionscan reduced the time needed to collect and analyze 20 samples from about five hours to 30 minutes. Forest Laboratories, which is currently implementing Ionscan for its cleaning verification, says it reduced the time needed for each product batch from 1.5 days to 4 hours, Sandor says

In addition Glaxo Smith Kline found that it took technicians a total of 55 minutes to set up and use Ionscan, generate results and have them approved, compared with four hours for HPLC, Sandor says. For each application within the company, Glaxo expects Ionscan to save some $38,480 in labor costs per year, in addition to the savings from reduced downtime. Assuming a cost of $90,000 for the instrument, and leaving downtime out of the equation, the device would pay itself in 2.3 years, according to the company. Smith's technology already has been deployed in analytical labs, and the company expects the systems to move into pilot, and, eventually, full-scale manufacturing operations.

If speed is HPLC's drawback in cleaning validation, ion spectrometry also has its limitations. First, Sandor says, the technology will only work with compounds that are volatilizeable and below about 1200 AMU molecular weight, so it won't work with many biological molecules. However, he says, the technique can be easily applied to 80% of the compounds used in pharmaceutical manufacturing. Both Smith's and GE are pursuing air monitoring applications, and Smith's Sandor foresees applications in raw material identification, content uniformity and dissolution testing.

Clean Rooms/HEPA Filtration

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HEPA stands for High Efficiency Particulate Air filter. HEPA filters were developed as a part of the Manhattan Project used to remove radioactive contaminants from the air in the development of the atomic bomb. After this type of filter was declassified by the government, the Cambridge Corporation was started to market and sell this technology. Camfil Farr Company has since acquired the Cambridge Corporation and their HEPA products and technology. dp filters has been a representative for the Camfil Farr Company and their product lines since 1973 and we have amassed a great amount of knowledge in this field.

HEPA filters are usually used in two types of situations, but there are numerous other applications which will not be mentioned. One is a clean room, where the goal is to remove as much particulate from the air as possible. Clean rooms are used in the manufacturing of electrical components where a single spec of dust can ruin the entire circuit board. Computer chips, computer hard drives, motherboards, cellular phone components, and a vast array of electronic components are a few examples of the type of manufacturing where HEPA filters are a must.

The second use of HEPA filters are in the healthcare industry. In these applications the goal is to have a sterile environment. A spec of dust will not do as much damage as long as it is sterile, but it easier to remove the particulate than it is to sterilize it. Also, working with hazardous items such as the AIDS virus, the TB virus, e. coli bacteria, and many other deadly bacteria and viruses for the sake of research, requires HEPA filtration. Most pharmaceutical companies have vast operations requiring HEPA filtration from their research departments to their drug production line and finally their packaging departments. Some hospitals use HEPA filters over surgical tables and in their TB isolation areas.

HEPA filters are manufactured in different efficiencies from 95.0% to 99.997% depending on the need. The efficiency is determined by the amount of particles the filter will remove from the air. Camfil Farr has a HEPA filter which will remove 99.997% of particles the size of 0.12 microns from the air, which is actually classified as an ULPA filter. A grain of salt is between 20 and 40 microns in size, so you can see the level of filtration we are talking about. Pollen is about 10 microns in size which is barely visible to the human eye, and bacteria, such as e. coli, ranges from 0.6 to 15 microns in size.

At Camfil Farr each filter is individually tested and certified for efficiency and initial resistance by state-of-the-art testing technology; use of a penetrometer for 0.3 micron hot DOP test (DOS testing available), or dual laser spectrometer for tests at specific particle sizes. In addition, automatic scanning equipment is used to verify leak-free filters. For more stringent requirements, other methods are available. Documentation of test data is supplied on individual labels on each filter enclosing frame and a letter of certification is available for every filter. If you are not requesting test results and certification for each of your HEPA filters, it would be wise to start doing so to make sure your supplier is up front about the quality of their products.

A Closer Look at Form-Fill-Seal Technology

Today, a growing number of pharmaceutical manufacturers are using advanced aseptic processing technologies to minimize operator intervention and contamination risk in the filling and packaging of liquid parenteral drugs. One of these technologies is form-fill-seal (FFS), in which a polymeric material is formed and sealed inline to a container of choice, while the container is being filled.

FFS offers cost savings over conventional aseptic processing in glass. Traditional parenteral filling and packaging requires 23 steps and individual machines for filling, stoppering and capping. In contrast, FFS requires one piece of automated machinery, and takes place in six seconds or less.

The entire FFS process is performed under a class-100 laminar flow, preventing external contamination. The fully automatic, computer-controlled technology allows for filling and packaging of up to 40,000 bottles of IV fluid per day. Nitrogen purging options are available for sensitive formulations such as amino acids.

Sterilization is achieved through an automatic, microprocessor controlled, circulating water-shower. The water becomes sterile during the process without any hazard to the product. The pressure/temperature link controls the whole process. The system uses a nylon filter medium to remove colloidal silica, pyrogens, mycoplasma, viruses and other contaminants.

A typical FFS process works as follows.

• First, bulk solution prepared under aseptic conditions (as appropriate) is delivered to the machine through a bacteria-retaining filter. Pipework, filter housings and machine parts that are in contact with the product are steam sterilized in place.



• Filtered compressed air and granules of a plastic material conforming to a predetermined specification and known to be compatible with the product to be filled (usually polyethylene, polypropylene or polyethylene/polypropylene co-polymers) are supplied to the machine.



• Within the machine, the plastic granules are extruded downwards under pressure (up to 350 bar) as a hot hollow moldable plastics tube (or “parison”) or tubes. As a result of the high pressure extrusion process, the parison reaches a temperature of 170° - 230° C. The configuration and internal integrity of the parison are maintained by an internal downward flow of filtered air under pressure.



• The two halves of a mold close around the parison to seal the base. Simultaneously, the top of the parison is cut free by a hot knife-edge. The plastics material is now formed into a container(s) by vacuum and/or sterile air pressure.



• The container(s) is/are immediately filled with a metered volume of the solution, displacing the sterile air. Both the air and the solution are filtered through bacteria-retaining filters immediately before entry into the forming, or formed container(s).



• When the required volume is filled into the container(s), the filling unit is raised and the containers are sealed automatically. The mold then opens, releasing a package formed, filled and sealed in one continuous, automatic cycle. Meanwhile, parison-extrusion continues, and the cycle repeats. The filled and sealed units usually require some cropping of excess plastic.

When used for aseptic manufacturing, the cycle is conducted automatically within the machine’s own internal sterile air flushed environment (or air shower). The range, accuracy, reproducibility and response time of all controlling and recording instruments associated with the FFS machine and all supporting equipment, must be adequate to ensure that defined process conditions will be consistent during routine production. All instruments must be calibrated before any meaningful operational qualification can be performed. Written calibration procedures should specify the methods to be used for each instrument. Recalibration should be carried out after any maintenance, and all records maintained. New machine specs should state requirements for:

• Materials of construction for all components, particularly all contact parts, such as machine pipe work; internal components of purchased fittings like automatic valves including elastomeric and mechanical seals; pipeline joint seals; welding materials; filters and filter housings including casing and substrate layers of cartridges, as well as the main medium and all elastomeric seals; and polymer extrusion equipment.

• Pipe work configuration, with attention to sterile fluid pathways — for example, the elimination of “deadlegs”; position of thermocouples (“as installed” configuration, verified against the original design configuration and confirmed by temperature mapping is typically part of the validation protocol); and filter housing design.

• Porosity of the product and air filters. The validation data from the filter manufacturers should be available.

• Mold design, considering fill volume range, wall thickness, opening characteristics and ease of use, shape and other aesthetic considerations.

If FFS machines are used for the manufacture of non-sterile products, FDA’s current Good Manufacturing Practices (cGMP) requirements should be followed. When used to manufacture products intended for subsequent sterilization, these machines may be installed within an environment that would normally be considered appropriate for the manufacture and filling of terminally sterilized products. If the machines are to be used for the aseptic filling of sterile products they are usually provided with a localized environment at the point of fill with Grade A air.

The Installation Qualification process for any FFS system should confirm and certify that the room conforms to the specified Environmental Standard. A new cleanroom installation should include: room air filter integrity tests; determination of air velocity at the face of each air inlet filter; room air change rate; air particle counts, both viable and non-viable, in the rest condition; room pressure differentials; and lighting, heating and humidity readings.

Following the initial commissioning, a regular re-test program should be adopted. Some of these tests include:

• Room Air Filter Test at least once a year

• Air Velocity twice a year.

• Air Particle Counts: Determine as part of regular in-process monitoring with formal certification by a competent specialist agency twice a year.

Room pressure differentials should be monitored on an ongoing basis. Walls, floors and surfaces should be subject to a pre-determined program of cleaning and disinfection.

A complete, on-going maintenance program should be developed and implemented. Matters to be specifically covered in the maintenance program should include those items listed under “Equipment Qualification.” In addition, examination and replacement of elastomeric seals, and the condition of molds, dies and pins should be monitored. The program applies to all supporting equipment and instruments as well. An in-process control and monitoring program is necessary for environmental particulates, filter integrity, microbiological concerns and product control. The environmental air should be checked so that it remains in conformity with the specification. The immediate air shower environment also should conform to specifications during processing with respect to viable and, where possible, nonviable particulate matter.

Filter integrity testing is needed for the filter(s) that are used to sterilize the product, and the filter(s) used to ensure the required air quality within the FFS machines. The internal air shower and container molding process is critical in sterile product manufacturing. Filter integrity tests of the product filter must be conducted after each and every use of the filters. It is recommended that filter integrity testing be performed before the filtration of the product commences and after the batch, or lot, has been filtered.

The following points should be considered for microbiological monitoring and control procedures:

• Bioburden check on bulk solution, before delivery to the FFS machine.

• Exposure of “settle plates” (petri dishes of nutrient agar) at critical positions within the general room where the machine is sited.

• Use of air sampling devices to determine the number of viable organisms per cubic foot of air in the room.

• Use of contact plates and swabs to see the microbiological quality of surfaces. Once filling is finished, operator entry into the machine room should be kept to a minimum. Operator “finger dabs” provide an additional microbiological control.

In-process, the product should be continuously checked for appearance, fill volume, wall-thickness of container, container leaks and container opening characteristics. This entire in-process monitoring program should be conducted as per the schedule and written specified test limits and standards. All results should be reported and evaluated formally against those limits.

The Table below lists the major process parameters and their risk to package integrity. All of these parameters affect the packaging process.

Regulatory Issues

The regulatory guidance recommends that FFS machinery and its surrounding barriers be designed to prevent the potential for extraneous contamination. In addition, a validated steam-in-place cycle or equivalent process should be used to sterilize the equipment path through which the product is conveyed.

The guidance also notes that the classified environment surrounding form-fill-seal machinery should generally meet Class 100,000 (ISO 8) or better. HEPA-filtered or sterile air provided by membrane filters should also be used when sterile products or materials are exposed. Air in the critical area should meet Class 100 (ISO 5) microbiological standards during operations. Finally, a well-designed system should achieve Class 100 (ISO 5) airborne particle levels.

Limitations of FFS

Volatility and viscosity are two limiting factors of FFS technology. If the solvent is volatile in nature (e.g., alcohol, if alcohol content is more than 5%), then FFS technology is not appropriate. However, a FFS machine with an explosion-proof design can fill solutions with alcohol content up to 95%. Viscosity also can be an obstacle. Slight warming may temporarily reduce viscosity enough to allow filling.

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References

1. Agalloco, J., Akers, J and Madsen, R., “What is Advanced Aseptic Processing?,” Pharmaceutical Manufacturing, February 2006, p. 25.

2. Berrebi, H., The bottle-pack system for the pharmaceutical industry, pub. Rommelag AG, Hintere Bahnhofstrasse 78, CH-5001, Aarau, Switzerland.

3. Leo, F., Chapter in Aseptic Pharmaceutical Manufacturing - Technology for the 1990s. Ed. Olson and Groves. pub. Interpharm Press.

4. Sharp, J.R., “Manufacture of sterile pharmaceutical products using ‘blow-fill-seal’ technology,” Pharmaceutical Journal, 1987, 239, 106.

5. Sharp, J.R., “Validation of a new form-fill-seal installation,” Manufacturing Chemist, Feb. 1988, p.22.

6. Zimmerman, L., “Technical measures for aseptic packaging of liquids with the ‘bottlepack-asepticsystem.’”

7. www.sandiacre.com

8. www.pmb-uvaine.com

9. www.manufacturers.com

10. www.boschpackaging.com

About the Authors

All authors are affiliated with the S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Kherva, Gujarat, India.

Rakesh Patel is an Assistant Professor in the Department of Pharmaceutics.

Gayatri C. Patel is currently working as a lecturer in the Department of Pharmaceutics and Pharmaceutical Technology.

Nikunjana A. Patel is currently working as a lecturer in the Department of Pharmacognosy.

Dr. Madhabhai M. Patel is Principal and Head of Department of Pharmaceutics and Pharmaceutical Technology.

Mobile Isolators Drive Kentucky’s New Aseptic Facility

In the summer of 2004, six men met at a Princeton, N.J. hotel to brainstorm a new aseptic filling facility for the University of Kentucky’s Center for Pharmaceutical Science and Technology (CPST): CPST managing director, an expert in business turnarounds, Frank Manella; Mark Gilbert, an expert in potent drugs who would manage the facility; and consultants Troy Fugate, Michael Perciali, David Matsuhiro and James Agalloco.

They emerged four days later with an ambitious plan: a sterile filling suite that could accommodate both potent and non-toxic compounds, in the same room at the same time. “We all hated corridors and walls,” says Manella. “It was all wasted space as far as we were concerned.”

Their vision will take shape this fall, when the new CPST facility, which was dedicated May 1, will open for business at the Coldstream Research Campus in Lexington. Sure, the facility may have a few corridors and walls, but it’s unlike any filling suite you’ve ever seen. The key to the design is mobile isolator technology, which allows product to be shuttled back and forth between contained process equipment via transfer boxes on wheels.

View from the front: Kentucky's Center for Pharmaceutical Science and Technology’s (CPST) new sterile clinical drug manufacturing facility.

Mobile isolator technology has only been around for three or four years, and has only been implemented at a handful of sites, notably Therion Biologics (Cambridge, Mass.), notes Hank Rahe, technical director for Indianapolis-based EnGuard Systems, which designed and manufactured the mobile isolator network used at the CPST. “It’s a technology for existing facilities and smaller companies that don’t have hundreds of millions of dollars,” he says.

Filling goes something like this: Product enters the suite within one of the transfer isolators, whose doors are closed in a sealed attachment that has been decontaminated with vaporized hydrogen peroxide (VHP). The transfer box is docked with another isolator, such as that surrounding the vial filler, and the area within is disinfected via VHP before the internal doors are opened and product transferred.

Once complete, the doors are again shut and sealed, prompting another decontamination cycle. A single transfer takes approximately 40 minutes, and is repeated from station to station — as stoppers are ferried from autoclave to filler, for example, or vials moved from filler to capper or, for freeze-dried products, to the lyophilizer. Once product is sealed and capped properly, a discharge isolator carries it outside the aseptic core for labeling and secondary packaging.

Transfers are the hardest part of using the technology, says Rahe. Before mobile isolators were developed, the only way that manufacturers could link isolators was through rapid transfer ports (RTPs). “But RTPs doors must be round to work,” says Rahe, “and the [pharmaceutical] world we live in isn’t round.”

Isolation challenges

The vial filler, autoclave, depyrogenation oven and lyophilizer are the most critical pieces of equipment on Kentucky’s fill/finish line. Each presented its own containment challenges, since conventional isolators and standardized equipment could not be used for this project.

With the filler, the challenge was to ensure that the mounting table could accommodate the isolator, Rahe notes. The table had to be expanded and the surfaces made smooth for easy cleaning. EnGuard had worked with OEM Chase-Logeman Corp. (Greenville, N.C.) to design and build such a table at Therion so that, at Kentucky, it could provide detailed specifications to filler-maker Bosch Packaging Technology (Minneapolis).

The filler isolator has two chambers, Rahe notes, one above the mounting table and one below, which houses the equipment’s mechanics. The upper chamber has a positive pressure, the lower negative. Should a rotating shaft or other piece of mechanical equipment leak, the pressure differential assures that contaminants will flow toward the negative pressure, maintaining the ISO Class 5 environment above.

The autoclave, manufactured by Steris Corp. (Mentor, Ohio), presented challenges as well. The door to the equipment slides behind a fascia, so the Kentucky team worked with Steris to ensure that the fascia was sealed properly and that VHP could access all surfaces during cleaning.

To fit within its isolator, the Hull (Warminster, Pa.) lyophilizer was outfitted with a narrow, horizontal “pizza door” — something Rahe had worked with Eli Lilly to develop several years ago — into which vial trays are slid and then indexed up or down on a chain system. The trays may be placed several deep, making them hard to reach and presenting an ergonomics issue. Operators will use glove ports to access a variety of reaching tools — such as a stainless steel rod and hook — to maneuver the back trays.

Drawings and specs weren’t enough

Vendors were given strict guidelines on how their equipment should integrate with the other pieces on the line. Drawings and specifications were not enough. The OEMs used wooden templates as guidelines for sizing and bolt placement. One company would mark up a template, then ship it on to the next. For all of the equipment, Kentucky personnel joined in on factory acceptance tests (FATs).

“What’s on drawings is never what ends up on the equipment,” says Gilbert. “You can’t be off even an eighth of an inch.” Much to his surprise, it all worked. “We did not have to do any customizing on the floor,” he says.

That’s not to say there weren’t some roadblocks here or there. Some of the equipment arrived late, after the Coldstream facility had been completed. A wall had to be knocked down to move the late equipment in, and then rebuilt. It’s okay to lose a day or two to get things right, Gilbert says. The trick is not letting any hitch or hiccup delay a project for weeks or months.

The system is designed for the smaller, varied batches that Kentucky aims to produce, but could also be used in some large-scale manufacturing operations where flexibility is critical. “Product transfers via the mobile isolators are time consuming,” Agalloco says. But the ability to change processes quickly and to shift equipment on the fly — to change from vial- to syringe-filling, for example — may appeal to nimble manufacturers, especially those who contract their services.

However, at this point, mobile isolators won’t permit classic 600 vial-per-minute operations, Rahe notes. The physical movement required typically limits production to 100 vials a minute, he says, though integrating the mobile isolators with a more stationary, traditional set-up might allow for up to 300 a minute.

M. William Garrett, CPST's pharmaceutical engineer, utilizes one of the mobile isolators in the facility's filling suite.

Flexibility is clearly mobile isolation’s biggest selling point. All equipment except the filler is on wheels. Because one piece is not bound to another, operators can start one batch while finishing another. Some of Kentucky’s clients may wish to have access to processes and machinery and choose not to use the isolated equipment, in which case it would be set aside and new pieces brought in. Still other clients will rent out the facilities to do their own manufacturing. “When you’re a contract facility and not sure who your customer is going to be, you have to design your facility differently,” Gilbert says.

While the filling suite itself is a Class 100,000 area, the isolators themselves retain a Class 100 status to support most aseptic processes. “It’s the essence of what Food and Drug wants to see in using barrier technology for parenteral products,” says Rahe. Agalloco sees the facility as the model for the future of sterile-fill pilot plants.

“The isolators provide a level of containment that allows you to do things, side by side, that you could never dream of in a conventional facility,” he says.

For all this, the 20,000-square-foot site was built on a $17 million budget. Several design and construction firms passed on the project, saying it couldn’t be done that cheaply. Eventually, CH2M Hill Lockwood Greene (Spartanburg, S.C.) signed on and has kept costs in line with expectations.

Future costs should not be extravagant either. In fact, Agalloco says, operations, labor, energy and environmental monitoring costs are all lower for isolators than they are for other technologies.

Up and running

Kentucky’s new facility illustrates a growing trend, as more universities get into the drug-making business (see Drug Manufacturing Goes Back to School, below), functioning as business incubators and magnets for top scientists and researchers. The university has made small batches oral and topical products in its college of pharmacy in Lexington since the early 1990s.

The CPST is a for-profit department within a not-for-profit university, with the operational proceeds considered “residual revenue” that is used to pay off debt or reinvested. Several years ago, UK hired an outside market research firm and determined that there was a clear niche for sterile-fill contract manufacturers that could produce in the neighborhood of 5,000 vials per campaign — greater than the capacity of a basic compounding pharmacy, and well below the capacity, and cost, of larger CMOs.

Most of its business is through fixed-price agreements with academics who need drugs for research or clinical trials, the National Institute of Health, and small biotech and pharma companies that don’t manufacture their own products, or don’t do in such limited quantities. The flexibility to serve many masters is key.

Along with the fill/finish area, the 20,000-square-foot building at Coldstream will have two formulation suites, a prep room, and analytical/micro labs, as well as office and warehouse space. Five air-handling systems are required in order to maintain differential pressure and separate room classifications between the formulation suites (Class 10,000, or ISO Class 7), fill/finish area (Class 100,000, or ISO Class 8), lab areas, offices and warehouses. “It’s not the most efficient way to do it,” says Gilbert. “But if somebody adjusts the [setting for the] cleanroom, it’s not going to impact all my lower classifications.”

Gilbert hopes to manufacture about 100 batches per year, or more if there is enough demand to warrant a second shift. The manufacturing staff will number just 10 to start out, with an increase to 35 as soon as possible. About half would be shop-floor operators from the local community, or even post-doctoral students from the college of pharmacy seeking practical experience.

Final validation completed

Coldstream’s core project team has just completed final validation of the facility and is conducting media fills in anticipation of its first products. Just getting to this point is an achievement, especially given the regulatory risk of putting cytotoxic and non-cytotoxic drugs in the same room. Before it put a shovel in the ground, Kentucky contacted FDA and laid out its plans before proceeding. From then on, it has worked closely with the Agency’s Cincinnati office on each step of the project.

FDA’s input has been invaluable, says Manella, especially in determining how the facility would be designed and processes validated. Once operational, it will be managed by a Quality Systems Group of five who will oversee QA, QC, document control and other validation and compliance efforts.

CPST's microbiology laboratory is equipped with a biosafety cabinet (left) and an EnGuard Systems sterility testing isolator.

For process validation, Kentucky will rely upon the practice of concurrent verification, essentially doing the testing necessary to prove the validity of a process and safety of the product with each batch. “Our customers only have enough API to do one batch,” says Manella. “The idea of validation is essentially impossible for a start-up company.”

A client may only want 5,000 vials, for example. Once it’s been manufacturered, the site will do a media fill and other testing to ensure sterility, and include everything in detailed batch records — often up to an inch thick, Manella notes. Customers get the high degree of assurance that they expect, and can use the information to simplify validation efforts as they scale up.

There are plenty of other issues that the CPST continues to address as it ramps up for production. Training is one. It’s no easy feat getting operators up to speed on such specialized equipment and processes. The plan, says Gilbert, is to do a trial run on a non-sterile product. “We’ll operate it like it needs to be sterile, so operators can train with no real risk to product,” he says. SOPs are still a work in progress. “I like to see what we write down actually work,” says Gilbert.

And there are still decisions to make on the computer systems that will control and monitor processes within the new facility. Gilbert specified Allen-Bradley PLCs as standard so that all future systems would easily interface with one another. One system in place is a Continuum building automation system from Tour Andover Controls (North Andover, Mass.).

Process control will be kept fairly basic, Gilbert says. “The isolators are fairly simple and don’t need a lot of control,” he says. “They’re pretty much just boxes with filtering systems and fans.”

One vendor has donated a package tailored for process analytical technology (PAT) applications, says Gilbert, but at present he doesn’t have the manpower to install, validate and reap its benefits. “We haven’t made formal product yet,” says Gilbert. “We’re not going to put too many things in the facility until we have our processes down.”

Whatever the future brings, the facility will adapt. “Most aseptic facilities don’t change much without pain and suffering,” says Agalloco. “Here, you can change bits and pieces easily while maintaining production and without disruption.”

How to Succeed with Mobile Isolation

Hank Rahe on EnGuard Systems offers tips on the design and installation of mobile isolators technology:

• Put someone in charge of the isolator integration. You can’t simply buy a piece of equipment and isolator and hope they come together.



• Watch out, since some manufacturers specify too high a level of laminar air flow within an isolator, he says. The standard is 90 feet of air per minute, but there is little scientific basis for that number. Within isolators, the risk of outside particulates is minimal, so modest air flow directed towards the exhaust makes more sense.



• Maintain clear and open communication at all stages of the project, especially regarding details during the final stages when people are rushing towards completion.



• Define the scope of the project, and bring vendors in from the start, even during the planning stages.



• Distinguish, as early as possible in the process, between the essential elements and the “nice-to-haves.”

Can We Break Down the Isolation Barriers?

Aseptic processing expert and consultant Jim Agalloco is not one to beat around the bush. His vision of the future pharmaceutical facility is one that has immense potential—in terms of advanced automation and robotics, and eliminating human intervention into the processing environment—but his enthusiasm is dampened by the realization that manufacturers won’t embrace technological change in the future any more than they have in the past.

PhM: Your vision of the future is one of automated processing environments free from human intervention. How can we get there?

J.A.: It’s a matter of taking the technology that’s already there and using it. I don’t think that we need to invent new stuff, that there’s anything out there that we don’t yet have. To some people it sounds crazy, because we don’t see this kind of high-end automation a lot. Someone just needs to have the foresight—or maybe that’s not the right word—the audacity to say, “It’s time.”

PhM: But there are plenty of people out there who have legitimate reasons for not pursuing the kinds of technology that you’re talking about.

J.A.: You know what, we make our own challenges. We make our own barriers to innovation all the time in this industry. There are other industries that are using technologies a heck of a lot more than we are. Electronics is a perfect example. Do people use robotics to make their processes more efficient? Absolutely, all the time. And yet we are paralyzed. You don’t see robotics and a lot of high-end technologies in use on our part.

It’s a huge mistake. The opportunities and technologies are there, we just don’t embrace them. We’re very comfortable using not just last year’s but last century’s technologies.

PhM: For some, there’s not a clear ROI to be audacious and to try something new.

J.A.: That’s an assumption they’re making. What is the cost of labor in our country? It’s pretty high, and could we not use machines to offset that labor cost? Why is it okay for the automobile industry but not for us? What’s our downside? We don’t really know what the downside is, we just think there is one.

PhM: There are regulatory hurdles, of course.

J.A.: I think [FDA and other regulators] are ready to embrace it. They’ve gotten to a point of understanding that they know this is a way to make processes safer by taking the operator out of the equation. If we believe that operators are the source of contamination, why wouldn’t they jump on opportunities to take the operator out of the environment?

PhM: Certainly there are manufacturers out there that are pushing the envelope?

J.A.: There are a few, but not nearly as many as there needs to be. Take a trip to Japan, anywhere in Japan. You see robotics and all kinds of things going on where they’ve brought the labor content way down.

We don’t do that. We do it in fits and starts. We do it slowly. Is there any poster child I can point to? None that I can point to, and that’s sad.

PhM: You see an “unmanned operation” as feasible then?

J.A.: Absolutely. Why not? What would prevent us other than our own prejudice?

PhM: What about contract manufacturers? Do you see them being more aggressive in adopting these technologies?

J.A.: I see them as less aggressive. They’re too squeezed financially. A lot of them attract business simply by being low-cost producers. I see them as technological laggards.

PhM: Are the vendors themselves pushing these technologies enough?

J.A.: How far can you be ahead of your customers? That’s the problem. That’s holding them back. If there’s no market for something, they’re opposed to pushing something faster than the market is ready to accept it.

Are there visionaries there? Yes, there are ideas. There’s people doing stuff that are ahead of the game. [Agalloco mentions a few vendor companies that have advanced isolation technologies, such as Canadian firms ATS Automation Tooling Systems and VanRx, and Belgium’s Aseptic Technologies.] At what point do we take that step? Do we just go along forever at this mediocre level of technology that we think is high-tech? We’re not even close.

PhM: So what are a few pieces of advice that you would have to move people towards using more advanced aseptic technology.

J.A.: First thing I’d say is, “Look in the mirror.” There’s your contamination source. If you acknowledge that first, then you can fix it. People don’t really accept that they’re as big of a problem as they really are. We tolerate lower-tech technology than we should because it’s convenient to have Mike or Susan in the cleanroom, but that’s not where we’ve got to be.

Then I’d tell people, look at your cell phone, look at your automobile. They’re so inexpensive these days. The cost to manufacture cell phones is practically free. How is that possible? With automation. With technology. Why are we afraid of it?

Sure, there are a few products like orphan drugs that don’t lend themselves to major investments in automation, but there are a lot of monsters out there that could really use it.

I’m very frustrated. I see what could be, but we’re moving very, very slowly. . . . I wish I could be optimistic but I’m not.

What is Advanced Aseptic Processing?

Over the last few years the term “advanced” has been applied to a number of aseptic manufacturing technologies. The 2002 open conference on sterile products co-sponsored by USP and PDA made advanced aseptic processing a discussion point, representing, we believe, the first such discussion in a public forum. At that time, only two “advanced” aseptic technologies were discussed: isolators and blow-fill-seal. Recently, an advanced technology that fills product into a sealed sterile container has been introduced, and restricted access barrier systems (RABS) have been termed “advanced” aseptic technology.

We believe that industry and the regulatory community should use the term “advanced” very conservatively in conjunction with aseptic processing, if it is not to become a commercial catch phrase. Performance limitations must be considered carefully. To avoid further hyperbole and misunderstanding, we propose the following definition:

An advanced aseptic process is one in which direct intervention with open product containers or exposed product contact surfaces by operators wearing conventional cleanroom garments is not required and never permitted.

The following examples would fit this definition:

1. Isolators, since they are effectively sealed against the entry of external contamination by means of air over-pressure. Isolators also allow decontamination to be performed in a quantifiable manner, and use gloves or half-suits to separate the human operator and the environment. Finally, all transfers of materials are done through RTPs, decontamination tunnels or pass-throughs.



2. Blow-fill-seal systems, provided that direct human interventions are not required during the filling/sealing process.



3. Closed-vial filling systems, provided there are no interventions into the critical zone where the filling needle(s) and post-irradiated closure surfaces are exposed prior to filling.

The common theme in these examples is that no direct human interventions are allowed at any time.

Critical distinctions

One could argue that it is possible to have human interventions in isolators, and in many isolator designs this is true. However, isolators are true separative enclosures with no direct entry by human operators wearing conventional cleanroom garments. All interventions are, instead, made through decontaminated gloves and sleeves or half-suits.Under no circumstances should an isolator enclosure be opened and a gowned operator allowed to work directly within the critical zone.

We believe that this distinction is critical, because studies have shown that gowned operators — even when using the best garments and technique — may release several thousand colony-forming units into the surrounding environment during each hour of work [1, 2]. Any technology that allows this level of interventional activity, and the potential for contamination associated with it, is too risky to be considered advanced.

Closed-vial filling systems, such as this one by Aseptic Technologies (Les Isnes, Belgium), offer distinct advantages as long as they do not require operator intervention. The line features two main areas. On the left is the loading station, protected by laminar air flow. At right is a Restricted Access Barrier System, in which filling occurs. For filling, a needle pierces the stopper, which is then resealed by means of a laser.

Some blow-fill-seal systems require that operators clear plastic that has solidified on fill nozzles, thereby blocking liquid flow. In this case, blow-fill-seal could only be classified as an advanced technology if, after this type of intervention, the product contact equipment was re-sterilized in place and any potentially affected product segregated and destroyed. Once again, the requirement is clear: if direct human intervention with sterile components or product contact surfaces is allowed, without the ability to eliminate any risk from that intervention, the aseptic process cannot be considered advanced.

Sealed sterilized container systems are advanced, as long as they do not rely upon gowned operators. Obviously, the exterior of the seals must be kept sterile and the filling needles must not be contaminated. For these conditions to exist, neither the seals nor the filling needles can be affected by gowned operator intervention. Closed systems offer significant potential advantages for controlling contamination, particularly those that can be penetrated, filled and resealed without operator intervention.

The question of RABS

Somewhat controversial are RABS, a type of aseptic processing that has lately garnered significant interest. We are encouraged by efforts to provide a suitable working definition of these systems; however, we believe that many, if not most, RABS processes would not meet our proposed definition for advanced aseptic processes. In some RABS designs, operators could open the RABS enclosure if an intervention that could not be conducted through the glove ports were required. In such a case, disinfection using a sporicidal agent has been recommended following the intervention. However, even though this treatment would decontaminate surfaces, it would not address the principal route of contamination, which is personnel-generated and dispersed in the environment.

We are also concerned that such a critical intervention as disinfection by gowned operators could raise nearly as many issues as it endeavors to address. Obviously, residuals from this disinfection procedure and contamination from the personnel performing it would be important concerns. It is not clear to what extent a major line clearance might be required, and what subsequent interventions might be required to restore the system to operation.

Clearly, aseptic systems that use gray- or black-side maintenance come closer to the spirit of advanced aseptic processing: systems that eliminate direct intervention by gowned operators.

Some advocates have supported RABS as a more flexible and more cost-effective aseptic processing solution than isolators. We agree that such a solution is more flexible. However, we are not sure that RABS qualifies as a truly advanced solution, and we are not convinced that the technology would result in meaningful cost savings over time.

We fail to see how validation requirements for RABS systems could be reduced relative to those for isolators. In fact, should two distinct types of disinfection be required, the validation workload could not be less than with isolator systems, particularly when a conventional cleanroom background is required, with all that entails in terms of monitoring and process control.

Regulatory relief for advanced systems?

In summary, we believe the standard for advanced aseptic processing must be rigorous and reducible to one principle: no direct interventions by gowned operators at any time.

Systems that meet this definition are currently available, and they should be given some relief from conventional aseptic processing validation requirements. We suggest that quantitative risk analysis be recognized in lieu of traditional validation exercises when advanced technology is employed in aseptic processing. Because these systems minimize the risk from human contamination, requirements for monitoring their environments can and should be substantially reduced.

In the future, we will see even more advanced forms of aseptic processing that address the few residual risks that may exist in current advanced systems. Gloveless isolators are already in use in some aseptic processing systems within the food industry and it is not hard to imagine closed sterile container systems capable of operating in a gloveless, unmanned environment. Automation and robotics may enable engineers to create systems that operate in a fully unmanned environment either with or without an isolator enclosure.The key to advancement lies in the elimination — not the tolerance — of interventions.

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References

1. Reinmüller, B. Dispersion and Risk Assessment of Airborne Contaminants in Pharmaceutical Cleanrooms. Royal Institute of Technology, Building Services Engineering, Bulletin 56, 2001

2. Whyte, W. Reduction of Microbial Dispersion by Clothing, Journal of Parenteral Science and Technology, Vol. 39, No. 1, 1985, pp. 51-60

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About the Authors

James Agalloco, BSChE, MSChE, MBA, is president of Agalloco & Associates, a technical service firm to the pharmaceutical and biotechnology industry. He is a past president of the Parenteral Drug Association and served as an officer or director from 1982 to 1993.

Dr. Jim Akers is president of Akers Kennedy and Associates, a technical consulting firm based in Kansas City, Mo. Dr. Akers is a past president of PDA and has served on numerous task forces related to aseptic processing over the years. He is currently chairman of the USP Committee of Experts for Microbiology and Sterility Assurance.

Russ Madsen is president of The Williamsburg Group, LLC, Gaithersburg, Md., engaged in pharmaceutical consulting in CGMP compliance and auditing, quality systems, design review, aseptic processing and sterilization technology, and other areas. He has served as acting president of the Parenteral Drug Association and was senior VP Science and Technology. Before joining PDA, he was director, Technical Services for Bristol-Myers Squibb Co.

Aseptic Blow-Fill-Seal Technology vs. Traditional Aseptic Processing

Since its introduction into the North American pharmaceutical market more than 40 years ago, blow-fill-seal (BFS) aseptic processing has established itself as a highly efficient and safe system for the filling and packaging of sterile pharmaceutical liquids and other healthcare products, such as creams and ointments. BFS product usage has been widely established in the ophthalmic and respiratory therapy markets for some time, and lately BFS technology has been gaining increasing worldwide acceptance in the parenteral drug marketplace, replacing traditional glass vial processing in a growing number of applications.

BFS enables a container to be molded from plastic, aseptically filled and hermetically sealed in one continuous, integrated and automatic operation, without human manipulation. The process provides flexibility in container design and system changeovers, high volume product output, low operational costs and a high assurance of product sterility. The inherent safety of the process – packaging sterile products under aseptic conditions without human intervention – has led the FDA, and the United States Pharmacopoeia, to characterize BFS technology as an "advanced aseptic process", indicating its use as a preferred technology.

New advances in drug delivery, the desire to improve convenience in handling pharmaceutical products, growing emphasis on combination products, the increasing focus on protein-based drugs and other biologics, and tighter regulatory criteria on product safety, have focused more attention on BFS technology over traditional aseptic methods as a better solution for the sterile, aseptic processing of pharmaceutical liquids.

Traditional Aseptic Processing and Sterility of Pharmaceutical Liquids

Microbial contamination is a serious issue for companies manufacturing liquid pharmaceutical formulations. Such liquids are ideal growth areas for bacteria like Salmonella, E. coli and Staphylococcus, microbes that have been found in various liquid drug products. A supposedly sterile, but contaminated product may result in deterioration of the drug and loss of potency, pyrogenic reactions after administration to a patient – particularly in parenterals, infection of the patient and colonization of microorganisms in the patient with the risk of a secondary infection. Any microorganism, pathogen or nonpathogenic, found in a supposedly sterile pharmaceutical product is dangerous.

Drug manufacturers have pursued various methods of sterilizing packaging components, product ingredients and equipment in order to achieve a sterile product in its final form. One system used is traditional processing, followed by terminal sterilization, which involves initially filling and sealing product containers within a cleanroom environment. The environment is set up to minimize the microbial content of the product while it is being manufactured. Each component of the process – the product, container and closure – have a low bioburden, but may or may not be sterile. The product, in the final container, is subjected to a “terminal” sterilization process, such as heat or radiation. The most common method uses autoclaving with saturated steam under pressure.

Traditional aseptic processing allows a final sterile drug product to be achieved by individually sterilizing the containers, material and equipment in-process, resulting in a unified sterilized product. In traditional aseptic processing, the containers are either supplied cleaned and sterilized to the filling line, or they are cleaned and sterilized within the aseptic filling line. Plastic containers are usually washed, dried, sterilized and cooled before filling. Glassware containers, which have been the dominating packaging material for terminally sterilized and traditionally sterilized pharmaceutical liquids, are usually sterilized in-line, exposed to hot air at 350 degrees C while being passed through a Class 100 tunnel. A glass container temperature of 180 to 200 degrees C is adequate for achieving sterility.

Methods of sterilization used in aseptic processing include filtering the solution by dissolving it in a solvent, such as Water For Injection (WFI), where the solution is passed through a sterilizing filter or membrane. Filter sterilization is used where the component is soluble and likely to be adversely affected by heat. A variation of this method includes subjecting the filtered solution to aseptic crystallization and precipitation (Lyophilization) of the component as a sterile powder. Dry heat sterilization is another effective method for sterilizing components that are heat stable and insoluble. Irradiation can also be used to sterilize some components.

Aseptic processing handles components, materials and equipment in such a manner that foreign microbial and endotoxin contaminents that exceed pre-determined acceptable levels, are not introduced to the product stream. To this end, it is critical that all storage, conveying, filling and container sealing stages be carefully controlled at each step of the process to maintain sterility of the product. Traditional aseptic processing, involving filling open glass bottles or vials, requires that the manufacturer maintain aseptic conditions in critical processing areas at all times. Unfortunately, the majority of liquid drug product contamination over the past several decades has come about from products produced in traditional aseptic processing facilities. Personnel Intervention in Traditional Aseptic Critical Areas

Traditional aseptic sterilization involves handling and manipulation of the material, containers, and sterilization filling processes with human intervention, and therefore has a higher potential for contamination during processing. The FDA’s 2004 Guidance for Industry Sterile Drug Products Produced by Aseptic Processing states that the design of equipment used in aseptic processing should limit the number and complexity of aseptic interventions by personnel. Both personnel and material flow should be optimized to prevent unnecessary activities that could increase the potential for introducing contaminants to exposed product, container-closures or the surrounding environment.

Ordinary walking by a person emits roughly 10,000 skin particles per minute. Such particles can and do hold microbial contamination. A rip in a worker’s uniform, a momentary exposed wrist, a mask placed too low on the nose or physical contact with an open fill port will increase microbial contamination within a critical area.

According to the FDA’s guide, airborne contamination is directly related to the number of people working in a cleanroom and the level of congregation by personnel in areas where critical aseptic manipulations are performed. Isolation of personnel from these critical areas would eliminate the major source of contamination in traditional aseptic processing.

In traditional aseptic processing, changing or adjusting filling nozzles and heads necessitates the shutdown of the filling operation and requires re-sterilization of the entire equipment. This increases manual intervention in this critical area. Cleaning and sterilization which is carried out by personnel, opens the door to breaching of established procedures for microbial decontamination and potential introduction of other particulates like dirt, oil and chemicals.

Mold is common flora found on floors, walls and ceilings of buildings. Contamination occurs due to the retention of water in cracks, edges and joints that are susceptible because of inadequate sealing. Brooms, mops and anything used for cleaning can become contaminated and increase atmospheric contamination because of raised dust or splashing water. In traditional aseptic processing, significant manual intervention is required in critical areas to maintain compliance with established sterile mandates.

Advanced Blow-Fill-Seal Aseptic Technology

In advanced aseptic BFS processing, containers are formed from a thermoplastic granulate, filled with a liquid pharmaceutical product and then sealed within a continuous, integrated and automatic operation without human intervention.

Bulk solution prepared under low bioburden or sterile conditions is delivered to the machine through a product delivery system that has been previously sterilized using an automated steam-in-place process.

Modern BFS machines are fully automated, designed to require minimum human access and operate in a classified environment using the following steps: (a) granules of a polymer resin, conforming to a predetermined set of specifications, such as polyethylene, polypropylene, co-polymers or other blow-moldable resins, are pneumatically conveyed from a non-classified area into the hopper of the BFS machine, from which the plastic is fed into a multi-zone rotating screw extruder which produces a sterile homogenous polymer melt (160–250 degrees C); (b) then to a parison head which produces hollow tubular forms of the hot resin (called parisons). The parisons are prevented from collapsing by a stream of sterile filtered support air. Some high-speed BFS machines have up to sixteen parisons being formed simultaneously; (c) container mold(s) close around the parisons, and the bottom of the parison is pinched closed, while the top is held open in a molten state; (d) the container is formed in the mold by blowing sterile air or creating a vacuum; (e) filling needles deposit the stipulated volume of product into the container; (f) the filling needles are withdrawn, and the upper part of the mold closes to form and seal the upper part of the BFS container; (g) the mold is opened and the completed, filled containers are conveyed out of the BFS machine to a remote station where excess plastic is removed and the finished product is then conveyed to final packaging.

Various in-process control parameters, such as container weight, fill weight, wall thickness and visual defects provide information that is monitored and facilitates ongoing process control.

The forming, filling and sealing steps are achieved in one unit operation – the cycle being completed within seconds. Automation of BFS process steps eliminates manual intervention and reduces risk to the product. No production personnel are present in the filling room during normal operation.

Microbial and Particulate Integrity in the Aseptic Blow-Fill-Seal System

Sterility of BFS polymeric containers, materials and processes is validated by verifying that time and temperature conditions of the extrusion, filling and sealing processes are effective against endotoxins and spores.Challenge studies have been conducted on the sterility levels of advanced BFS technology, which demonstrate a uniform capability of achieving contamination rates not exceeding 0.001 percent throughout the entire process. Even higher sterility assurance levels, approaching 0.000001 percent, have been achieved using high levels of airborne microbiological challenge particles.

Endotoxins are a potential pyrogenic contaminant, essentially dead bacterial cellular matter. They can lead to serious reactions in patients, particularly with those receiving injections, ranging from fever to death. A critical aspect of BFS technology is its pyrogen-free molding of containers and ampoules. Extensive experiments confirming the efficacy of the BFS extrusion process have been performed using high levels of spores and endotoxin-contaminated polymer granules. The typical BFS extruders have demonstrated spore contamination rates of 0.000001 percent, and 0.00001 percent for endotoxins.

Control of air quality is critical for sterile drug product manufacture. BFS equipment design typically employs the use of specialized measures to reduce microbial contamination and particle levels that can contaminate the exposed product. The BFS process inherently produces a very low level of particulate matter and much of potential BFS microbial contamination (viable) in the air is mitigated by the absence of manual intervention in its critical areas. Non-viable particles generated during the plastic extrusion, cutting, and sealing processes are controlled. Provisions for carefully controlled airflow protect the product by forcing created particles outward while preventing any inflow from the adjacent environment. These “zones of protection” can also incorporate designs that separate them from the surrounding environment, providing additional product protection.

The BFS critical processing zone is continually supplied with HEPA-filtered air by an air shower device (shroud). The BFS critical zone is the area where the containers are exposed during filling. Air in the critical zone meets Class 100 (ISO 5) microbiological standards during operations. The critical zone is continuously monitored to ensure a positive differential pressure is maintained between the shroud and the adjacent cleanroom.

Plastic vs. Glass Containers

Injectables, ophthalmics, biologicals and vaccines are produced in a number of different types of containers, including bottles, vials and ampoules that are made from glass and plastic. Protecting the contents of these aseptic liquid drugs through filling, packaging and transportation, and allowing for safe and easy administration are critical objectives in the aseptic process. The industry is infused with a strong quality control emphasis. Raw materials, and in-process and finished products are continually checked for approval and rejection.

The packaging needs for pharmaceutical liquids are quite demanding. It is not unusual for degradation of the product to occur during processing or while in transit. The physical properties of liquids can be altered with inadequate packaging components. For aseptic filling, the package must be produced, stored, filled and sealed under conditions that preserve sterility. Likewise, the appearance of particulates in sterile solutions is equally undesirable.

Glass, although a standard in the aseptic pharmaceutical liquids industry, is not without its limitations. There is the safety issue – glass vials are subject to breakage, both in transit and while being administered. Handling glass containers always involves a certain amount of risk of lacerations and glass splinters. Glass ampoules, for example, generate a fine array of small glass particles during opening.

Manufacturers using glass containers are also subjected to design limitations when the designs become somewhat complex. With glass containers, as design complexity increases so does the cost. Once glass containers are produced, they need to be transported to the aseptic facility. Glass is typically transported in cardboard boxes that can contain mold spores, such as Penicillin sp. and Aspergillus sp., as well as bacteria like Bacillus sp. Paper, also used in the shipping of glass, can also contain mold spores. The rubber closures used on the glass containers can have mold contamination.

Domestic drug companies have been slow to change to plastic, primarily due to the existing installed base of glass production of small-volume parenteral drugs in the United States. However, the same is not the case with new drugs that are coming onto the market. These are more frequently being looked at, and submitted for FDA approval, in plastic containers produced by advanced BFS aseptic processing. Supporting this move is that the BFS processing resins, polyethylene and polypropylene, are generally considered inert by the FDA. Many of the blow molding resins used in BFS processing have received international acceptance as suitable for food and drug applications, and many of the drug products produced outside of the United States can be found packaged with these resins.

With the continued refinement of BSF technology, its acknowledgment by the FDA as a preferred technology for aseptic processing, and its growing acceptance by drug companies, the migration from glass to plastic containers used for aseptic pharmaceutical liquids is growing rapidly. It has become more cost effective to use plastic containers for aseptic liquids, which effectively costs manufacturers one-third of the cost of glass. Plastic is less expensive to ship because the containers are lighter. For small-volume parenterals, the use of plastic is inevitable, and increasingly being considered for these reasons.Although many BFS systems make available only a limited number of container choices within each container category, some BFS machines do allow for broad versatility in container design. Advanced BFS machines can design virtually any container mold through the use of sophisticated CAD/CAM technology and 3-D modeling. These design systems, when interfaced with the latest in CNC and EDM machinery, ensure fabrication of key components to precise tolerances.

BFS machine designs also allow for mounting of separate sterile items (inserts) within the BFS container, and in-mold coding and engraving, which provide further opportunities for innovative design over that of glass products.

Flexibility with Changeovers Allows Shorter Runs, Increased Uptime, Maximized Throughput

Modern BFS system design is focused on simplicity and flexibility. Many BFS machines are configured to produce more than one bottle shape or format. This makes it easy to change over from one container size to another. A BFS machine might produce a family of 2, 3 and 5ml, then switch to a family of 5, 10 and 15ml, or to one of 10, 15 and 20ml, moving from one to the other with relative ease of machine set-up. This is ideal for manufacturers performing contract packaging of aseptic liquid pharmaceutical solutions, because of their need for changeover flexibility.

The growing usage of biologics is demanding packaging in different formats. They usually require smaller process runs and are typically heat sensitive. Many of these new biotechnological drugs do not withstand steam sterilization or irradiation and so are best treated aseptically. More advanced BFS machines have been designed so they can handle these heat sensitive products.

Machine models are available that can produce containers ranging in size from 0.1mL to 1000mL at production rates of 15,000 units per hour, depending on container configuration. BFS machine efficiency is very high. More advanced BFS machines can approach 99 percent uptime efficiency, which is significantly higher than traditional aseptic processing which is plagued with slow-downs in part because of manual interventions. To further minimize potentials of system downtime, some manufacturers are now segmenting their high-volume process lines into more short-run lines, in the event that if one of the lines goes down for maintenance or repair, it will not stop the entire production throughput.

When aseptic throughput is interrupted, or not running because of downtime, the entire process line is affected, which represents a significant production loss to the manufacturer.

An Aseptic Technology Destined to Prevail

More rapid container closure processing, elimination of aseptic critical-area personnel interventions, increased system uptime over traditional processing, pyrogen-free molding of containers and ampoules, more flexibility with container design, and an increased capability to capitalize on short runs - these are some of the benefits for manufacturers inherent in advanced blow-fill-seal aseptic technology. And for the consumer, increased safety and confidence in their drug products are strong additional benefits.

These are advances that are significant, if not fully realized yet within the aseptic liquid pharmaceutical marketplace. But it is apparent that advanced BFS aseptic technology is destined to become a major player in this arena.