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THE IMPORTANCE OF EMPLOYING GOOD OPERATIONS, MAINTENANCE AND PERSONAL PRACTICES IN CLEAN ROOM MANUFACTURING BY: Wayne Kenny

Clean Rooms

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THE IMPORTANCE OF EMPLOYING GOOD OPERATIONS, MAINTENANCE AND PERSONAL PRACTICES IN CLEAN ROOM MANUFACTURING

BY: Wayne Kenny

Date: 16/03/10

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TABLE OF CONTENTS

Executive Summary:.........................................................................................1, 2, 3,4

Introduction.................................................................................................................5

A Brief History of Clean Rooms, ................................................................................5

Environmental Control...................................................................................6,7,8,9,10

Monitoring............................................................................................................11,12

FDA Warning Letters...........................................................................................13,14

Cleaning, santization and sterilization........................................................................15

Quality System ..........................................................................................................15

Maintenance...............................................................................................................16

Conclusion.................................................................................................................16

References 17

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Executive Summary:

The history of clean rooms dates back to Atomic Age and greatly enhanced in the Space Age. However, its roots go back hundreds of years to Swiss watchmakers who, to prevent dust from falling on their sensitive timepieces when they were not being worked on, covered them with a small bell jar. In the 1960 Willis Whitfield pioneered the clean bench, a means of conducting clean work in a small space. To keep a room very clean, let air be the janitor — a“janitor” sweeping the premises every six seconds.[2] This new technology was embraced by the sterile manufacturing industry as a means of compliance of GMP. In the late 1960’s and early 1970’s regulatory authorities had become more stringent. The main drive for this is not that the regulators are making new rules but rather technology has improved industries ability to address key issues in the regulatory world. Thus, the concept of the term “current” in current Good Manufacturing Practices is a reality which can be demonstrated when new technologies come into play, they change the nature of industry practice and thus change what is current from a regulatory view.

The costs for poor operations, poor maintenance and poor personal practices in clean room manufacturing can be high in both financial and regulatory terms. Poor CGMP conditions at a manufacturing facility can ultimately pose a life-threatening health risk to a patient. All manufactures of medicinal products have to ensure that they products are fit for their intended use, comply with the requirements of the marketing authorization and do not place patients at risk due to inadequate safety, quality or efficacy. This is in effect a quality objective. To achieve this one must have a correctly implemented system of Quality Assurance incorporating CGMP(FDA 2l CFR parts 210 and 211) and thus Quality Control.These regulations,for the most part, describe what needs to be accomplished rather than how to accomplish the requirement.

On how to accomplish them we must first understand what a clean room is, a cleanroom is a controlled environment where products are manufactured. It is a room in which the concentration of airborne particles is controlled to specified limits.. These contaminants are generated by people, process, facilities and equipment. They must be continually removed from the air. To employ good operations one has to build quality into the premises and control the environment.

FDA 21 CFR 211.42(c) states, in part, that "Operations shall be performed within specifically defined areas of adequate size. There shall be separate or defined areas or such other

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control systems for the firm's operations as are necessary to prevent contamination or mixups during the course of the following procedures (10) Aseptic processing, which includes as appropriate: (iii) An air supply filtered through high-efficiency particulate air filters under positive pressure; (iv) A system for monitoring environmental conditions; (vi) A system for maintaining any equipment used to control the aseptic conditions." [1] 21 CFR 211.46(b) states that "Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product." [1]

21 CFR 211.46(c) states, in part, that "Air filtration systems, including prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas."[1]

The areas of manufacture must have a separate unit of operation that control to different degrees, depending on what is being done, the air quality. The design of an area should be based on satisfying microbiological and particle standards defined by the equipment, product exposure, as well as the operation in the area. Particles are significant because they can enter a product and contaminate it physically or by acting as a medium for microorganisms. The control of this is achieved by HVAC systems Cleanrooms are designed to achieve and maintain a airflow in which essentially the entire body of air within a confined area moves with uniform velocity along parallel flow lines. This air flow is called laminar flow. The more restriction of air flow the more turbulence. Turbulence can cause particle movement. Filtration is used such as HEPA(High Efficiency Particulate Air Filter)- These filters are extremely important for maintaining contamination control. They filter particles as small as 0.3 microns with a 99.97% minimum abilty to collect particles. In addition to the HEPA filters commonly used in cleanrooms, there are a number of other filtration mechanisms used to remove particles from gases and liquids such as membrane filters which allow the filtering of compressed gases to meet an appropriate high-quality standard. These filters are essential for providing effective contamination control.

21 CFR 211.42(b) states, in part, that "The flow of components, drug product containers, closures, labeling, in-process materials, and drug products through the building or buildings shall be designed to prevent contamination."[1]

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. Any intervention or stoppage during an aseptic process can increase the risk of contamination. Thus the use of automation and good engineering that increase process flow and reduce product handling should be incorporated.

21 CFR 211.25(b) states that "Each person responsible for supervising the manufacture, processing, packing, or holding of a drug product shall have the education, training, and experience, or any combination thereof, to perform assigned functions in such a manner as to

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provide assurance that the drug product has the safety, identity, strength, quality, and purity that it purports or is represented to possess."[1]

A well-designed aseptic process minimizes personnel intervention. As operator activities increase in an aseptic processing operation, the risk to finished product sterility also increases. To ensure maintenance of product sterility, operators involved in aseptic manipulations should adhere to the basic principles of aseptic technique at all times. Personnel can significantly affect the quality of the environment in which the sterile product is processed. Due to this personal micro monitoring should be carried out.

21 CFR 211.22(c) states that "The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product."[1]

Evaluating the quality of air and surfaces in the cleanroom environment should start with a well-defined written program and scientifically sound methods. The monitoring program should cover all production shifts and include air, floors, walls, and equipment surfaces, including the critical surfaces that come in contact with the product, container, and closures. SOPs should be established in such areas ash as (1) frequency of sampling, (2) when the samples are taken (i.e., during or at the conclusion of operations), (3) duration of sampling, (4) sample size (e.g., surface area, air volume), (5) specific sampling equipment and techniques, (6) alert and action levels, and (7) appropriate response to deviations from alert or action levels.

21 CFR 211.56(b) states that "There shall be written procedures assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules, methods, equipment, and materials to be used in cleaning the buildings and facilities; such written procedures shall be followed."[1]

21 CFR 211.100(a) states that "There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit."[1]

All in-process data must be included with the batch record documentation.. Review of environmental and personnel monitoring data, as well as other data relating to acceptability of output from support systems (e.g., HEPA / HVAC, WFI, steam generator) and proper functioning of equipment (e.g., batch alarms report; integrity of various filters), should be viewed as essential elements of the batch release decision.

The implemtation of a live and active quality system incorpating CGMP will ensure compliance. This is further reinforced by the FDA taking a “risk assessment” approach to enforcement of the regulations. This means that the agency will target those products that

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reflect the greatest threat to the safety of public health. Sterile dosage forms will be high on the list.

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Introduction

This article will show that employing good operations, good maintenance and personal practices are essential in clean room manufacturing. The consequences of non compliance of CGMP has the possibility of being financially large, i.e. loss of market share, loss of public confidence, loss of the business. It is a legal requirement to implement CGMP of the marketing authority. It is more importantly a morale issue that could pose a treet to human life. Due to this compliance is of utmost importance.It can be achieved based on a correctly implemented system of Quality Assurance incorporating CGMP(FDA 2l CFR parts 210 and 211 or other marketing authority CGMP) and thus Quality Control.The article will follow FDA regulations followed by the means and the ‘know how’ on achieving compliance.It will draw on the Regulations, Quality Assurance, Warning letters from FDA and some antidotal evidence.

A Brief History of Clean rooms

The field of contamination control is a recent technology coming to age as part of the Atomic Age and greatly enhanced in the Space Age.[2] However, its roots go back hundreds of years to Swiss watchmakers who, to prevent dust from falling on their sensitive timepieces when they were not being worked on, covered them with a small bell jar.The American Civil War) gave impetus to the next phase in cleanliness. Due to the immense loss of life from bullet wounds, surgeons recognized the need for steps to prevent post traumatic infection. Lister and others developed methods to achieve this end and sterility became a watchword in operating suites.In 1945 the need to test gas mask filters against particulate and biological materials led to the development of the aerosol particle counter.The final step, the development of the High Efficiency Particulate Air (HEPA) filter was developed at Sandia Labs for the Atomic Energy Commission after World War II. Nuclear particles which would have been deadly to personnel were isolated in process areas with HEPA filters while allowing air to circulate in them. Willis Whitfield pioneered the clean bench, a means of conducting clean work in a small space.[1] White rooms had been used during W.W.II to assemble contamination-sensitive parts such as gyroscopes. These rooms used filtered air but not as highly filtered as HEPA air.

Finally, the Space Age with its requirements for both particulate and film cleanliness promoted contamination control technology. Through the 60's documents such as FED STD 209a, NASA SP-5076, "Contamination Control Handbook", NASA SP-4074, "Clean Room Technology", NASA SP-5045, "Contamination Control Principles", and AF-TO-00-25-203, "Contamination Control of Aerospace Facilities, US Air Force"[2] were written. These documents stated principles which are still relevant today.

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The pharmaceutical industry embraced this new technology as a means of compliance of regulatory authorities drive of CGMP in the same period.

Environmental Control

FDA 21 CFR 211.42(c) states, in part, that "Operations shall be performed within specifically defined areas of adequate size. There shall be separate or defined areas or such other control systems for the firm's operations as are necessary to prevent contamination or mixups during the course of the following procedures (10) Aseptic processing, which includes as appropriate: (iii) An air supply filtered through high-efficiency particulate air filters under positive pressure ***; (iv) A system for monitoring environmental conditions; *** (vi) A system for maintaining any equipment used to control the aseptic conditions."[1] 21 CFR 211.46(b) states that "Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product." [1]

21 CFR 211.46(c) states, in part, that "Air filtration systems, including prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas[1]

Clean rooms have to be separate to other operational procedures. The microbiological impact have to be incorporated into the design of the space. Room finishes are hard and easily cleanable, minimal/no crevices. Material and personal flow are unidirectional in critical area’s. Equipment placement and ergonomics are important in maintaining product/process integrity and operator safety. Air Flow: unidirectional in critical operations to protect product exposed to the room environment. HVAC, controls, zoning, and pressurization are in place to protect product, control contamination,and keep people comfortable. The air is classified by the following tables:

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[5]

Achieving a compliant cleanroom manufacturing operation requires the use ofincreasing levels of environmental cleanliness, or “zones.” The figure below a typical zoning, along with a typical air pressurization cascade from critical to noncritical zones. In noncritical peripheral areas can be downgraded to a Controlled Not Classified (CNC), where the room is designed to meet Grade D performance parameters but is not typically validated.

To maintain air quality in areas of higher cleanliness, it is important to achieve a proper airflow and a positive pressure differential relative to adjacent less clean areas.The people and

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material flow are controlled by airlocks with alarmed doors. The diagram below demonstrates this in a Bio manufacturing plant

[4]

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Pressure cascade below:

[4]A differential of 15 Pascals between each air classifications. Controlled by airlocks.

To achieve this, the air most be filtered by HEPA filtration. Different areas of classification require different HEPA filters and membrane filters which allow the filtering of compressed gases to meet an appropriate high-quality standard. Gases used such as air, nitrogen, and carbon dioxide are often used in cleanrooms and are frequently employed in operations involving purging or overlaying. Sterile membrane filters should be used for autoclave air lines, lyophilizer vacuum breaks, and tanks containing sterilized materials. Holding tanks containing sterile product should be held under positive pressure to prevent micro biologicial growth

[3]The above diagram is unidirectional flow cleanroom with HEPA and membrane filtration in the ceiling. The number of air changes is determined by monitoring and justified for the area of classification. This is done by particle monitoring and velocity monitoring. Changes in velocity across the membrane of a filter can indicate a possibility of contamination. Leak testing should be performed on filters as part of continuous maintenance program.To detect integrity breaches around the sealing gaskets, through the frames, or through various points on the filter media. Thereafter, leak tests should be performed at suitable time intervals for HEPA filters in the aseptic processing facility. For example, such testing should be performed twice a year for the aseptic processing room.Smoke studies should be conducted that demonstrate unidirectional airflow and sweeping action over and away from the product. However, even successfully qualified systems can be compromised by poor operational, maintenance or personnel practices

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The cost of A zoning is high to run and maintain. So the thinking would be to reduce the A zoning area with barrier isolators. The diagram below illustrates this;

A zoning (criticial area) reduced with isolators above and below.[3]

[3]

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Adequately separating areas of operation is an important part of contamination prevention. To maintain air quality in areas of higher cleanliness, it is important to achieve a proper airflow and a positive pressure differential relative to adjacent less clean areas

Monitoring

21 CFR 211.22(c) states that "The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product."

21 CFR 211.42(c) states, in part, that "There shall be separate or defined areas or such other control systems for the firm's operations as are necessary to prevent contamination or mixups during the course of the following procedures: *** (10) Aseptic processing, which includes as appropriate: *** (iv) A system for monitoring environmental conditions***."

21 CFR 211.25(a) states that "Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee's functions. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them."

Environmental monitoring programs for clean room manufacturing are composed from the analysis of personnel, processes, raw materials,and finished products.Evaluating the quality of air and surfaces including personal in the cleanroom environment should start with a well-defined quality system and scientifically sound methods that are evaluated to ensure they operate as intended The monitoring program should cover all production shifts and include air, floors, walls, and equipment surfaces, including the critical surfaces that come in contact with the product, container, and closures. Written procedures (SOP’s) should include a list of locations to be sampled. Sample timing, frequency, and location should be carefully selected based upon their relationship to the operation performed. Samples should be taken throughout the aseptic processing facility (e.g., aseptic corridors, gowning rooms) using scientifically sound sampling procedures. Sampling sizes should be sufficient to optimize detection of environmental contaminants at levels that might be expected in a given clean area. Risk management should be incorporated to show area’s that pose the most microbiological risk to the product and become a critical part of procedures. It is especially important to monitor the microbiological quality of the aseptic processing clean area to determine whether or not aseptic conditions are maintained during filling and closing activities. Montoring should be from contact plates used for flate surfaces such as walls, ceilings,uniforms. Difficult surfaces can be swabbed or rinse swabbed.Settle plates for air. Air and surface samples should be taken at the actual working site and at locations where significant activity or product exposure occurs during

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production. Critical surfaces that come in contact with the sterile product should be sterile. When identifying critical sites to be sampled, consideration should be given to the points of contamination risk in a process, including factors such as difficulty of setup, length of processing time, impact of interventions. Critical surface sampling should be performed at the of the aseptic operation to avoid direct contact with sterile surfaces during processing. Personal are the highest risk in a clean room from both viable and non viable particles and hence ‘Gowning’. The table below shows gowning requirements for zoning area’s.

D Hair net, shoe covers, lab coat, (optional cover of facial hair)C Same as D but gloves and facial hair cover requiredB Same as C with a coverallA Same B but with facemask, boots, hood with three seals, neck, wrist, and ankles

Therefore training of personnel in aseptic techniques and proper gowning must be a priority. Routine microbiological monitoring of garments and finger impressions must be completed to determine general aseptic techniques. In general, microbiological sampling of the personnel includes contact plate samples of; right chest, left chest, forehead ,right sleeve, left sleeve,right hand glove covers and left hand glove covers. A program of evaluation of training and support procedures should be implemented. Sanitization of hands before and after every working day reduces the possibility of microbial contamination. Gloves are either sanitized or a new pair before testing the next sample. Hair and body must be cleaned daily. The use of cosmetics and jewelry are not allowed. Personnel with a contagious disease such as cold, flu, and pink eye must stay away from controlled environments.

Alert and action limits are established after sampling, analyzing, and trendingthe values obtained during at least 3 months of intensive microbiological testing of facilities and personnel[5]. Once the trends are determined, then limits are set upon historical, regulatory, and industry guidelines. Alert limits are values that when exceeded point towards a potential deviation from the system operating normally. Action limits values when exceeded show the system is in non compliance and an investigation report and corresponding corrective actions must be performed and implemented. Some companies operated that if 2-3 alert limits are exceeded that this constitutes action limits. If an investigation is needed to investigate any deviations from the established values, proper documentation of the investigation, and corrective action must be completed within reasonable time. These investigations are usually completedwithin 1–3 months. Improper or late closure of an investigation is one of the major reasons for noncompliance with CGMP regulations. The type of corrective actions that are implemented when an action level has been exceeded are typicially , sampling and testing are immediately repeated if conditions indicate that the product quality has been compromised. Sanitization procedures are reviewed and repeated. Retraining of personnel is performed if the investigation report indicates analyst error. Review of controlled environment certifications might indicate system breakdown during manufacturing, sampling, and testing. Basically, all thesystems and validation procedures are reviewed to determine the root cause ofthe action level. If there is an indication that the product manufactured has

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been compromised, the batches are placed on hold until the investigation is completed and the product is cleared for release.

An antidotal reference by a colleague who worked for An American company where one individual when de-gowning discovered a ‘cricket’ on his shoe beneath his shoe cover. As it was put ‘all hell broke lose’. Which no doubt covered the procedures above.

The FDA warning letter below enforces the points above.

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Cleaning, sanitization and sterilization.

21 CFR 211.56(b) states that "There shall be written procedures assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules, methods, equipment, and materials to be used in cleaning the buildings and facilities; such written procedures shall be followed."

While non-product contact, such as tables, racks, carts, etc, are cleaned at intervals, product contact equipment, such as tanks, pumps, piping, etc., must be cleaned more frequently (typically between product batches or change-overs).Product contact equipment also consists of fixed and portable equipment. Fixed equipment is disassembled with some components removed from the room for cleaning out of place (COP) in a purpose-built room. Remaining components are cleaned in place (CIP) by flushing the system with a series of solutions and rinses while the system is closed. Control of these fluids is managed by both the process equipment and a CIP system (typically a skid) control units.. As the equipment moves through the cleaning process, the surrounding environment increases in cleanliness to correspond with the state of the equipment being cleaned. This typically means that the room(s) will be designed to meet a Grade D/C environment, with localB/A.The non-product contact area’s should be cleaned and disinfected. The cleaning process should be validated and recorded. The disinfectant should be rotated. Sterilization of equipment that is product contact is done but must be proven that the system effectively kills all viable micro organisms. Equipment sterilized in place (SIP) is typically achieved through the introduction of pure steam in a closed system for a prescribed interval of time and temperature. Equipment that can not be sterilized in this manner are placed into grade A environment before process opertions. They are either either be chemically sterilized, irradiated, or purchased as being sterilized.The sterilization of the end product if possible should be ‘terminal sterilizated’ but not all products can be.Such methods as filtration, moist heat, dry heat, chemical vapours, and radiation should be employed.

Quality System

21 CFR 211.100(a) states that "There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit."

All in-process data must be included with the batch record documentation.. Review of environmental and personnel monitoring data, as well as other data relating to acceptability of output from support systems (e.g., HEPA / HVAC, WFI, steam generator) and proper

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functioning of equipment (e.g., batch alarms report; integrity of various filters), should be viewed as essential elements of the batch release decision.

MaintenanceEase of maintenance is of importance. Technicial area’s which allow access to maitance staff with out disruption to zoning. Clean rooms can have access to HVAC systems through walkable ceilings also instrumentioncan be housed there. Maintenance chases or grey areas can be employed for piping , valves etc and can be controlled unclassified. A sample can be seen below:

[4]

Conclusion;

A quality system incorporating CGMP will ensure continues compliance. But the system will ultimately fail if poor maintenance is carried out and could potentially endanger life. Maintenance should be schduled and preventive in nature which in turn will save money in down time. It should be recorded and well documented. Good maintenance is at the heart of the overall system i.e. HVAC, equipment etc. Personal practices are utmost importance as they pose the largest micro biological risk in a clean room operation. The number of people who are in the rooms should be kept to minimum, people intervention in the process should also be kept to minimum. Personal should be trained and evaluation of the training effectiveness should be established. Good operations encompasses the overall process. Manufacturing operations, according to CGMP, means that the process has a set of controls in the design and production processes to assure

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a quality finished product.

The financial cost for non compliance is huge, loss of market, plant closure, brand integrity etc. But more importantly is patient safety once this area is engraved into a quality policy and allowing the air to be the janitor, the rest will follow.

References

1. Code of Federal Regulations, Title 21, Food and Drugs, “Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs,” Part 210–211 (US Printing Office,Washington, DC, revised April 2000).

2.www.fda.gov/history.htm

3. Clean room design. By W.White. Published by John Wiley & Sons. 1999

4. Good Design Practices for GMP Pharmaceutical Facilities. Edited by A.Signore and Terry Jacobs. Volume 146.

5.Microbial Contamination Control in the Pharmaceautical Industry.Volume 142. Edited by Luis Jinenez.

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