Goals
When you have completed this unit, you should be able to:
a. Perform an audit of a calibration, preventive maintenance, and housekeeping system
b. Use a range of tools and information, including the contents of this unit and the internet to support the audit of a calibration, preventive maintenance and housekeeping system
c. Understand and apply appropriate GMP standards/regulations to an audit of a calibration, preventive maintenance and housekeeping system
d. Recognize compliance or non-compliance of calibration, preventive maintenance and housekeeping systems to applicable regulations
Definitions
Adjustment: The adjustment of an instrument to improve accuracy so it shows the correct value. It is recommended to calibrate before and after adjustment. See also calibration.
As found: The condition or status of equipment, instrumentation or systems prior to calibration or maintenance activities.
As left: The condition or status of equipment, instrumentation or systems following calibration or maintenance activities.
Calibration: The ICH definition is: “The demonstration that a particular instrument or device produces results within specified limits by comparison with those produced by a reference or traceable standard over an appropriate range of measurements.” A shorter definition is: “Calibration shows the error an instrument has when compared to a known standard.”. See also adjustment.
Critical item: Items which have been assessed to impact on product quality, safety and efficacy or otherwise present an unacceptable hazard if the equipment or its protective system should fail and where failure or malfunction could lead to danger to life, significant harm to any person or to the environment.
Housekeeping: Those activities designed to keep a facility in a clean, sanitary and well- maintained condition.
Inventory: the list of equipment for a facility, organized in a convenient hierarchy, with equipment identified at the level at which the maintenance history will be documented and maintained.
Maintenance: The combination of all technical, administrative and managerial actions during the lifecycle of an item intended to retain it in or restore it to a state in which it can reliably perform a required function. Maintenance can be planned or unplanned.
Normal Operating Range: The normal operating limits of the instrument, equipment or system as required for operation within a process.
Preventive Maintenance System (PMS): This system brings together people, equipment and procedures (including scheduled maintenance plans) to ensure that an asset is available for operation in accordance with its functional specification.
Process Tolerance: The limits within which a process parameter should be maintained to ensure adequate product quality.
Standards: measurement systems or artifacts, traceable to National or International Reference Standards, which are used to calibrate test equipment.
Test Equipment: Measurement systems used to calibrate critical instrumentation.
Traceability (General): The ability to trace the history, application or location of that which is under consideration (ISO 9000:2000).
Traceability (with respect to calibration): The ability to relate individual measurement results through a continuous sequence of measurement accuracy verifications, to nationally (or internationally) accepted measurement systems.
Explanation of Topic
Introduction
Calibration of critical items, preventive maintenance and housekeeping, while not appearing to be the most important parts of GMP, are vital to keep a site in compliance and producing quality product.
If an audit is being performed on calibration, preventive maintenance or housekeeping, the two GMP systems that should be reviewed during the audit are:
Ø Quality System
Ø Facilities and Equipment System
The site audited should have SOP(s) in place describing the overall calibration and maintenance program including:
Ø How critical items requiring calibration and maintenance are identified (a risk/GMP assessment should be in place for defining what is critical and not)
Ø Establishing calibration and maintenance requirements and review during item lifecycle
Ø Description of the workflow for calibration and maintenance
Ø Management of “out of tolerance” conditions and remedial actions
Ø Requirements for trend reviews /e.g. calibration failures, maintenance frequencies)
Ø Prevention from use of “un-calibrated” and “out of service” items
Ø Acceptance of items as suitable for use
Ø Use of contractor calibration and maintenance providers
Ø Documentation requirements
Ø Cleaning requirements when reintroducing/removing equipment to/from sterile areas or areas where hazardous materials are handled
Quality Unit/Quality Assurance
The site should have an established Quality unit/Quality Assurance department. One of the responsibilities of the Quality Unit/Quality Assurance should be to review out-of tolerance data to determine if it has impacted product quality. If it is determined that there has been product quality impact, the out of tolerance result should be classified as a deviation or Quality observation.
Calibration
Equipment and instrumentation routinely used in the manufacturing and QA laboratory areas need to be within calibration at all times during normal operation. To ensure this, each site should have a written approved calibration program which includes specific directions, schedules, calibration requirements, and provisions for remedial action if accuracy and/or precision limits are not met. Calibration requirements for each piece of equipment, instrument or system should be documented. The limits and parameters for the calibration should be established through a combination of:
Ø Process requirements (including accuracy/regulatory)
Ø Duty and location of instruments
Ø Qualification work
Ø Recommendations from the manufacturer
Ø Experience, history
The frequency of calibration should be recorded and determined using the same criteria as for limits and parameters. Once a frequency is determined it should be part of an approved maintenance and calibration schedule. If there is a question as to the interval of frequency, the smallest interval should be chosen that precludes any risk to the product.
Allowable time frames for calibration should be defined (e.g monthly ±3 days, quarterly ±7 days) and compliance with schedule verified. This schedule should be part of a procedure to manage maintenance and calibration.
Calibration status of equipment and instruments should be easily identified. Status may be indicated through a label visible on the instrument or equipment, through a database or other means. If an external contractor is performing calibration work for the site, the contractor must work with the Site Engineering and Maintenance group. Site personnel should also review and approve the calibration documentation and/or records generated by the contractor in order to ensure that jobs have been completed per established procedures and that equipment is within established tolerances.
If possible, calibration should be performed in a calibration laboratory, free of conditions that may impact calibration such as:
Ø Vibration
Ø Variable line –voltage
Ø Dust
Ø Fumes
Ø Extreme temperature ranges or other environmental extremes that could impact equipment functionality
All calibration work must be recorded. Calibration records normally contain the following information:
Equipment/Instrument Name and ID #
PMS Number ______________
Date calibration performed: ___________
Date of next calibration: _____________·
As-found readings: _________________
As- left readings ____________________
Description of work performed:___________
Test equipment (incl. certificates as appropriate) and standard used:________________
Procedure used: ________________
Additional documentation required to interpret the results _______________
Signed by _________________
(Person performing work)
Approval of records to assess any SHE or product implications following any adjustments.
Calibration records should be kept in a secure document filing and archive system.
Calibration data should be reviewed for trends. All work performed on equipment or instruments should be documented and use traceable standards. Computer systems for scheduling, tracking, and reporting of calibration and preventive maintenance jobs should be developed and implemented to defined quality standards with appropriate qualification performed.
Reference Standards and Trace ability
All testing equipment or standards used to perform calibration should be traceable to fundamental measurements standards as shown below.
Type of standard | Trace ability |
(Primary Reference Standards) | National Standard Organization, i.e., National Institute of Standards and Technology (NIST) |
(Secondary Reference Standard) | Standards Laboratory |
(Working Standards) | Company Instrument Laboratory; Process Instruments |
At appropriate intervals, secondary reference standards used in the standards laboratory should be calibrated against primary standards. Calibration can be performed either by a highly trained qualified internal group or a qualified external group.
If equipment or instruments are found to be out of calibration or out of tolerance, the site should have a system in place to ensure that they are not used. This may consist of labeling the equipment or instrument with “DO NOT USE-CALIBRATION REQUIRED” or similar wording, removing it from its location, entering its status into a database or other means designed to ensure that the equipment or instrument is not used. The reason for the equipment being out of calibration should be investigated. The investigation should include batches manufactured since the previous calibration, as well as an evaluation of product quality impact. The need to re-adjust calibration frequency should be evaluated
When the equipment or instrument has been calibrated, investigated, adjusted, recalibrated and determined fit for use through appropriate testing, it may be reinstated.
Special requirements may apply, e.g. reintroduction of equipment into sterile areas or where there are hazardous substances. Additionally where hazardous substances are handled equipment may need to be cleaned before removed to engineering shop or externally.
Anyone performing calibration, either a site employee, an external contractor working at the plant or an external contractor at a remote location is expected to be competent in the function that they are performing. Persons performing calibration must have documented training demonstrating qualification.
If calibration is performed at an external location, the calibrated equipment or instrument, when returned to the site, should contain documentation that includes, at a minimum:
Ø A statement of the trace ability to national or international standards
Ø The date, signature, and identification of the laboratory performing the calibration
Ø The as-found status reported by the laboratory performing the calibration
Ø The as left status of the instrument and whether this meets the acceptance criteria
Ø Reference to the procedures used
Ø Signature of the person who performed the calibration
Ø Test equipment certificates as appropriate
Raw data supporting calibration jobs should be retained in accordance with the site retention period schedule.
Preventive Maintenance
Preventive maintenance is considered planned maintenance. This maintenance is performed on equipment, instruments or systems to:
Ø Ensure equipment is able to operate normally within its specifications before an unplanned repair is needed
Ø Extend the operating life of the equipment or instrument
Ø Replace worn parts before they affect equipment or instrument performance which will affect drug quality
Ø Provide routine or recommended maintenance such as lubrication.
All preventive maintenance should be scheduled at sufficient frequency to ensure that equipment, instrumentation and systems, are within their operating limits under normal operating conditions. Frequency may be established through consideration and review of the following criteria:
Ø Work performed during qualification
Ø Frequency of use
Ø Experience and application
Ø Process requirements
Ø Criticality of device with respect to GMP impact
Ø Duty and environment of instruments
Ø Historical trend data
Ø Required accuracy of process
Ø Regulatory aspects
Ø Maintenance recommendations from the manufacturer
The rationale for the frequency of the preventive maintenance must be documented. The frequency should be on the conservative side by ensuring that no product is at risk because of infrequent maintenance.
The site should have an approved preventive maintenance schedule. A written approved procedure to manage calibration and maintenance according to the schedule should be in place. In the case of unplanned maintenance, the site should have a written procedure defining how to appropriately perform and document such work. The impact of unplanned maintenance on routine manufacturing needs to be assessed, documented and remedial actions taken.
When performing maintenance, planned or unplanned on equipment, instrumentation or systems, the maintenance must be documented. For routine or planned maintenance, the documentation normally contain (same record can also be used for unplanned work although some degree of diagnosis/investigation may also be needed):
Maintenance Record
Name and Identification (ID) of Equipment/Instrument:
_____________________
Date Performed: _______________
Date of next Preventive Maintenance _________
As-found Status: __________________________
As-left status: ___________________________
Maintenance/test equipment, spare parts, or other materials used: ___________________________
Procedure(s) used _________________________
Additional documents used __________________
Signed by ___________________
(person performing work)
If lubrication is required in the course of a preventive maintenance program, the lubricant should be kept out of contact with the drug product. Food grade lubricant should be used for maintenance activities. Depending on design of equipment/premises special requirements may need to be attended to in sterile manufacturing areas.
If the preventive maintenance requires replacement of parts, spare parts should be removed from the site’s controlled spare parts inventory. Only authorized personnel should be allowed access to spare parts, which may only be signed out by authorized personnel. If spare parts are used in the maintenance of equipment, instruments or systems, this must be documented on the maintenance record.
The replacement parts must clearly be “like-for-like” part replacement otherwise change control and potential validation activities may be needed. Critical items spare parts should only be sourced from an approved list of suppliers.
Calibration and maintenance jobs should not impact product quality. Calibration and maintenance jobs should be scheduled accordingly. Appropriate production personnel should grant authorization to work in manufacturing and packaging areas. Manufacturing equipment may need to be cleaned after maintenance using defined procedures. When maintenance has been carried out within a clean area, the area should be cleaned, disinfected and/or sterilized where appropriate, before processing recommences if the required standards of cleanliness and/or asepsis have not been maintained during the work
Use of contractors for calibration and maintenance
Site procedures should define the approach to management of calibration and maintenance performed by external contractors and calibration service suppliers, including requirements for contracts/service level agreements/shared SOPs. The roles and responsibilities of the contract acceptor and contract giver need to be defied in an appropriate written agreement. Delineation of responsibilities should be agreed.
SOPs should describe the provision of calibration and maintenance records or certificates by external contractors. This should include a review of work performed to verify that it has been completed to an acceptable standard, and approval by the site indicating that the appropriate acceptance criteria have been met.
Housekeeping of a facility
Housekeeping within a facility is designed to provide a clean, sanitary and well- maintained environment. Specific activities of housekeeping include sanitization and cleaning, removal of waste and general maintenance of the facility.
Rest and refreshment premises should be separate from other areas. Facilities for changing clothes, and for washing and toilet purposes should be easily accessible and appropriate to the number of users. Toilets should not directly communicate with production areas.
Sanitization and cleaning
The facility should be kept in a state of cleanliness commensurate with the activities and functions performed. To ensure this, there should be approved written procedures that include cleaning schedules, methods, equipment, sanitizing and cleaning agents, cleaning requirements, and materials. Cleaning and sanitization should be documented. Those personnel performing the cleaning should be trained and competent in the procedures appropriate to their function. If external contractors are used to perform cleaning, they should be trained to the same level and competency as internal personnel. Training must be documented.
The site should have a documented program for prevention of infestation from rodents, birds, insects and other vermin. This program should designate what rodenticide,
insecticide fungicide and fumicide can be used at specific locations within the facility to ensure that equipment, components and drug products are not contaminated. The personnel administering the program, either internal or external, should be thoroughly trained. If an external contractor is used, they should be supervised by a member of the site.
Removal of waste
There should be an approved written procedure in place for the safe and sanitary removal of waste. These procedures should include method of removal, frequency and disposition.
Personnel should be trained in the appropriate procedures. Disposal of pharmaceutical sensitive waste or critical components should be done in controlled and documented manner by a reputable supplier. Supplier should be included in the audit program.
General maintenance
The physical plant facility should be maintained in a good state of repair with no obvious physical defects. The facility should be well lit, unless there are special conditions requiring low lighting. It should be clean, well maintained, and uncluttered.
“Key Parameters in Auditing a Calibration, Preventive Maintenance and Housekeeping System”
Prior to the audit
Review the inventory list of the site’s critical equipment, instruments and systems.
Determine if there are any outstanding corrective actions from previous audits or regulatory inspections involving calibration and/or preventive maintenance of critical equipment, instruments or systems, or housekeeping citations.
During the audit
Inspect the facility/area for appearance and cleanliness:
Ø When arriving at the site look carefully around to get a first impression of maintenance and housekeeping and check for proper and controlled segregation of materials, i.e. waste not next to components or raw materials.
Ø Determine if the facility has any obvious problems (e.g. missing ceiling tiles, holes in walls, peeling paint, “stained” floors, trash overflowing etc.).
Ø Ensure that critical equipment and instrumentation within the facility has stickers or labels to indicate calibration status or has another system in place to indicate calibration status.
Ø Determine if the facility appears well maintained and visibly clean.
Ø Determine if there is any evidence of vermin infestation.
Review the quality system:
Ø Verify that there is an established and approved Quality System/Quality
Policy that is endorsed by management:
Ø Verify that the Quality Unit/Quality Assurance is independent of manufacturing.
Ø Verify that one of the Quality Unit’s/Quality Assurance responsibilities is to review out of tolerance results and determine the impact on product quality.
Ensure that personnel have received adequate training:
Ø Verify that there is a documented training and qualification program for any person responsible for conducting calibration, preventive maintenance or housekeeping.
Ø Verify that detailed job-specific training is conducted and documented for each employee.
Ø If external personal are used to perform the calibration, preventive maintenance or housekeeping function, ensure that they have been qualified and are competent.
Ø Verify that the training program incorporates requirements for temporary employees and consultants.
Ensure that there is a calibration program in place at the site:
Ø For calibration of equipment, instrumentation and systems, ensure that there is a written and approved program for managing calibration. This program should contain the following information:
An inventory of critical equipment, instruments and systems (including computer systems) requiring calibration should be available and include appropriate acceptance criteria.
Specific calibration requirements including limits and parameters for each piece of equipment, instrument or system.
The accuracy, precision and linearity of the calibration need to be relevant to the critical instrument and scale of measurements.
Frequency of calibration for each piece of critical equipment, instrumentation, or system.
Review system for issuing calibration schedule.
Determine timeframe within which calibration must be performed.
Determine what will happen if calibration does not take place as scheduled
Standards and testing equipment to be used in each calibration, which can be traced, back to a primary standard.
Methods to be used in each calibration.
Documentation for recording calibration results.
Calibration schedules.
Procedures detailing what to do in the case of an out of tolerance result.
Procedures for performing trends on calibration data.
A system for retention and retrieval of calibration history and data.
Requirements for using contractors.
Documentation that computer systems for calibration program management are validated
Ensure that there is a preventive maintenance program in place at the site:
Ø For maintenance of equipment, instrumentation and systems, ensure that there is a written and approved program for managing maintenance.
Ø Verify that the program contains the following information:
An inventory of critical equipment, instruments and systems (including computer systems) requiring maintenance.
Specific maintenance requirements including limits and parameters for each piece of equipment, instrument or system.
Frequency of maintenance for each piece of critical equipment, instrumentation, or system.
Methods to be used for maintenance.
Documentation for recording maintenance results.
Maintenance schedules.
Procedures for cleaning equipment after maintenance (and calibration) if necessary.
Procedures for performing trends on maintenance data.
A system for controlling the spare parts inventory.
The system used to communicate maintenance schedule
The timeframe within which maintenance must be performed.
Ø Verify that computer systems for preventive maintenance program are validated.
Ø Verify that in the course of preventive maintenance if lubrication is required that food grade lubrication is used.
Ensure that there is a housekeeping program in place at the site.
Ø Verify that there is a system for managing facility cleaning.
Ø Verify that there are written procedures that include:
a. cleaning schedules
b. methods
c. equipment
d. approved sanitization and cleaning agents
Ø Verify that cleaning is documented.
Ø Verify that the facility has a documented program for prevention of infestation from rodents, birds, insects, or other vermin.
Ø Verify that the site has a list of approved infestation prevention agents and uses only those
Ø Verify that the site locations for the prevention infestation (pest control) stations are placed logically, documented, reviewed on a regular basis for activity and any relevant recommended actions are implemented.
Ø Verify if a contractor is used for the prevention of infestation (pest control) then appropriate agreements are place and any visit reports are reviewed and approved.
Ø Verify that the site has adequate personnel, procedures and methods to ensure timely removal of trash and refuse from the site.