A. Equipment Cleaning for Drug Products

B. Identification of Equipment Areas and Processes

C. Equipment Cleaning for Active Pharmaceutical Ingredients (APIs)

D. Calibration

E. Preventative Maintenance

F. Cleaning and Sterilization of Aseptic Manufacturing Equipment

G. Areas and Facilities Cleaning and Maintenance

H. Pest Control

I. Water Purification, Storage, and Distribution for Pharmaceutical Production

J. Air Handling Systems & Air Classifications for Aseptic Operations

K. Clean Steam Systems

L. Aseptic Area Environmental Control

A. Equipment Cleaning for Drug Products

This practice document defines general cleaning requirements for facilities and equipment for Drug Products.

This practice applies to all GMP Production Sites where drug products are manufactured and/or packaged for Pharmaceutical and Animal Health.

Product Contact Equipment, both Major and Minor, used in production, Subdivision, or sampling of a drug product, In-Process Material, or Raw Material (RM) shall be cleaned and shall include, and not be limited to:

* Changeover Cleaning;

* Interval Cleaning during a Campaign, as necessary; or

* Dedicated Equipment Cleaning at the end of a campaign. Equipment disassembly may be required to clean or to Verify cleanliness.

Equipment Cleaning for major equipment must be conducted following written Instruction-Records or Standard Operating Procedures (SOP) with an attached checklist(s). These documents shall be Approved by the Site Production Team and Site Quality Team before being issued.

Equipment cleaning for minor equipment shall be conducted following written SOPs or Instructions-Records and these cleaning activities must be documented. The SOPs and Instruction-Records shall be approved by the Site Production Team and the Site Quality Team before being issued.

Executed Instruction-Records or checklist used shall be reviewed and approved by the Site Quality Team. Use and Cleaning History must be determined for product contact equipment that has been used by third parties or by another facility (e.g., trials, rentals, borrowed). The history must be documented and approved by the Site Quality Team. The removal of previous product residues must be verified, prior to any use.

The history shall demonstrate that the equipment was not used for and does not contain potential contamination from objectionable materials (e.g., penicillins or other beta lactams, pesticides).

Equipment Cleaning shall be designed to prevent Cross Contamination including microbiological contamination, when applicable [based on the Risk Assessment, by reducing residues on all product contact surfaces to acceptable levels. Maximum Allowable Residue (MAR) and Residue Acceptability Limit (RAL) for Equipment Cleaning shall be established by Qualified personnel based on the empirical data and the approved calculation method, prior to any use.

Swab or Rinsate Sampling Methods must be Validated through use of recovery studies. The Analytical Methods used to test for residue must also be validated. For Changeover Cleaning, Routine Verification of Cleaning Processes for Major Equipment Where One Hundred (100) Percent Visual Inspection is not Possible shall include:

* Inspection to the extent practical to verify the equipment is Visibly Clean;

* Periodic monitoring (e.g., using swab or rinsate sampling method as per validation) at a frequency defined based on a documented and approved risk assessment (e.g., up to 2 to 3 years) of the probability of contamination; and

* Approved justification of the rationale for the frequency of the periodic monitoring.

Routine Verification of Cleaning Processes for Major Equipment Where One Hundred (100) Percent Visual Inspection is Possible shall include inspection to verify the equipment is visibly clean (e.g., mills, filter housings, and tray driers).

Lighting shall be sufficient to facilitate visual inspection for residues. For areas to be visually inspected, the equipment must be dry before inspection.

Routine Verification of Cleaning Processes, for minor equipment shall include visual inspection to verify the equipment is visibly clean.

Lighting shall be sufficient to facilitate visual inspection for residues. For areas to be visually inspected, the equipment must be dry before inspection.

If the Only Verification of Cleaning Processes to be Conducted on a Piece of Equipment is Visual, then the visually detectable quantity must be known and documented.

A Qualified Individual other than the one who performed the cleaning must verify that the equipment is visibly clean.

Commercial Production Equipment, for a one time product (e.g., clinical Batches/Lots), for which cleaning has not been previously validated, must be verified as clean by visual and residue testing after the production of the product, before the next use of the equipment.

The Need for Cleaning, Type or Level of Cleaning, and Cleaning Frequency within a Campaign shall be defined, and documented.

Interval cleaning shall be performed as required during a campaign. Product Changeover Cleaning Procedures must be validated for all product contact equipment used for multi-product production and sampling of drug products.

Personnel Responsible for Equipment Cleaning Operations and Sampling must be trained and qualified in these operations. Such training, along with Evidence of Training Effectiveness, shall be documented.

Approved Cleaning and Sanitizing Agents shall be used to clean product contact equipment and shall be compatible with the surfaces to be cleaned. These agents shall be purchased, received, stored, approved, dispensed, and transferred similarly to raw materials (RM).

Equipment Cleaning, Use, and Maintenance Logs, consisting of chronological entries on sequentially numbered pages or equivalent validated electronic System, shall be maintained for each major Equipment Unit, and for each major Equipment Item that is not included in a defined equipment unit. Information to be recorded shall include, and not be limited to, the following:

* Documentation of cleaning, use, and maintenance;

* Date of the activity;

* Start and finish times of the activity;

* Equipment use, including product name and Batch Numbers or Lot Numbers of each lot or batch processed in the equipment;

* Signature or initials of individual performing the work; and

* Signature or initials of a second person verifying the work, where no other primary Records are in place to document the work.

For non-electronic based equipment cleaning records, use and maintenance logs, the issuance, revision, retention and reconciliation of pages must follow Site procedural control as per primary records, such as batch records.

For Each Equipment Unit or Item, the Cleanliness Status shall be indicated using labels and/or signs or a centralized paper-based or validated electronic system. Cleaning status can only be changed to “clean” once all monitoring results (when applicable) are obtained and found to be satisfactory. Examples of equipment cleaning status include, but are not limited to:

* Hold for Cleaning,

* Cleaning, and

* Clean.

Measures to Protect Clean Equipment must be taken during storage to prevent environmental or microbial contamination. For example:

* Store equipment dry,

* Close tank openings,

* Close tablet machine covers,

* Cap or cover open flanges, and

* Protect portable equipment (major and minor) from environmental exposure by sealing in a protective bag or by shrouding and storage in a clean location.

Cleaned Portable Equipment must be stored, segregated from, in-use and/or unclean equipment.

Pre-Use Inspections shall be performed immediately prior to use following a changeover cleaning or dedicated equipment campaign cleaning, and documented (e.g., in the next batch or campaign record). Pre-use inspection shall verify that the equipment:

* Has been properly assembled (e.g., via visual inspection or by communication with the responsible personnel);

* Has been cleaned;

* Is visibly clean;

* All identification from the prior product has been removed;

* Cleaning records are verified for completion;

* Analytical results (if applicable) are satisfactory; and

* Maximum allowable time period between cleaning and next use was not exceeded (if applicable).

Maximum Allowable Time Intervals for Periods Between Use and Initiation of Cleaning shall be evaluated. If this time period potentially impacts the ability to clean the equipment then the time period must be specified and validated.

If the maximum allowable time intervals are exceeded, the equipment must be re-cleaned and inspected prior to use. If applicable, the equipment shall also be sampled (e.g., for potential microbiological contamination). The re-cleaning and cleaning verification shall be documented (e.g., logbook, cleaning instructions or checklist).

After Completion of any Maintenance or Instrument Calibration Activities that required opening or disassembly of equipment, an evaluation must be conducted and documented to determine the level of cleaning required, if any, for product contact equipment.

Prior to Being Put into Service, New Equipment shall be cleaned and, the equipment shall be verified as visually clean at a minimum. The cleaning and verification of cleanliness must be documented and approved prior to use.

Equipment Cleaning Failures During Routine Monitoring (i.e., visual and/or analytical result failures) must be documented and Investigated according to established Site procedures. An evaluation of the impact on validation must be included.

B. Identification of Equipment Areas and Processes

Distinctive Equipment Identification Numbers or Codes shall be displayed clearly and prominently on all Areas and Major Equipment that involve, or are directly related to Production, and shall be used for referring to that equipment in all such documents as manufacturing, packaging, cleaning, and maintenance Instruction-Records, and in corresponding equipment logs and other similar records.

All Rooms and Areas Used for Production shall be identified at all times by function (e.g., filling room, blending room, packaging area, crystallizer room) and/or room number.

During Processing, Materials, Processing Vessels, Major Equipment, and Rooms that are involved in the process must be labeled or otherwise clearly identified (e.g., barcodes,

Computerized Systems) with an indication of the product or material being processed including, and not limited to the following information:

* Name of the product or material being processed;

* Strength, if applicable;

* Batch Number or Lot Number;and

* Stage of production (e.g., crystallization, drying, blending, filling), when applicable.

Processing and/or Storage Vessels and their associated manifolds, filling, and discharge lines shall be identified in a manner designed to preclude incorrect use of the lines.

Fixed and/or Dedicated Processing Lines, Piping, and Other Conveying Devices that provide liquids or gases to production or control areas shall be clearly identified as to the contents and the direction of flow in a manner designed to preclude incorrect use of the lines.

Status Indication Measures shall be used with all products and materials. Cleanliness Status of Major Equipment and Minor Equipment shall be displayed for API, for drug products, and for medical devices.

C. Equipment Cleaning for Active Pharmaceutical Ingredients (APIs)

Product Contact Equipment, both Major and Minor, used in Production of an Active Pharmaceutical Ingredient (API), Intermediate or Raw Material shall be cleaned including, and not limited to:

  *         Changeover Cleaning;

*           Interval Cleaning during a Campaign as necessary in both dedicated and non-dedicated equipment; or

*           Dedicated Equipment Campaign Cleaning.

*           Equipment disassembly may be required to clean or to Verify cleanliness.

Equipment Cleaning must be conducted following written Instruction-Records that shall be Approved by the Site Production Team and the Site Quality Team before being issued.

Maximum Allowable Residue (MAR) and Residue Acceptability Limit (RAL) for cleaned equipment shall be established by Qualified personnel based on empirical data and the approved method of calculation.

Use and Cleaning History must be determined for product contact equipment that has been used by third parties or by another facility (trials, rentals, or borrowed). The history must be documented and approved by Site Quality Team. It must be verified that previous product residues were removed prior to any use. The history shall demonstrate that the equipment was not used for and does not contain potential contamination from objectionable materials (e.g., penicillins or other beta lactams, pesticides). Equipment Cleaning as described in instructions-records shall be designed to prevent Cross Contamination by reducing residues on all product contact surfaces of equipment to acceptable levels.

Swab or Rinsate Sampling Methods must be Validated through use of recovery studies. The Analytical Methods used to quantitate the residue must also be validated . If the Only Verification of Changeover Cleaning Processes to be Conducted on Equipment is Visual, then the visually detectable quantity must be known and documented. Compounds that are published as Generally Recognized as Safe (GRAS) are an exception to this requirement.

For Changeover Cleaning, Routine Verification of Cleaning Processes for Major Equipment, Where 100 Percent Visual Inspection is not Possible, shall include:

*           Inspection, to the extent practical, to verify the equipment is Visibly Clean; and

*           Residue no more than the RAL where required.

Cleaning between steps of the same API process shall be evaluated to determine the level of cleaning and/or verification required (e.g., interval cleaning may be appropriate between sequential steps of the same API process). The approach taken at the Site shall be documented and approved by the Site Quality Team.

Routine Verification of Cleaning Processes for Major Equipment Where 100 Percent Visual Inspection is Possible shall include inspection to verify the equipment is visibly clean (e.g., mills, filter housings, reactor charge chutes, and tray dryers). Lighting shall be sufficient to facilitate visual inspection for residues. For areas to be visually inspected, the equipment must be dry before inspection.

Routine Verification of Cleaning Processes for Minor Equipment shall include inspection to verify the equipment is visibly clean. Lighting shall be sufficient to facilitate visual inspection for residues. For areas to be visually inspected, the equipment must be dry before inspection.

A Qualified Individual, other than the one who performed the cleaning, must verify that major equipment is visibly clean.

The Need for Cleaning, Type and/or Level of Cleaning, and Cleaning Frequency Within a Campaign shall be defined and documented. Interval cleaning shall be performed and documented as required during a campaign.

Product Changeover Cleaning Procedures must be Validated for all product contact equipment used for multi-product production, Subdivision, and sampling of APIs and those intermediate steps subsequent to the introduction of the API Starting Materials into the process.

Personnel Responsible for Equipment Cleaning Operations and Sampling must be trained and qualified in these operations. Such training, along with Evidence of Training Effectiveness, shall be documented. Changes to validated cleaning procedures and any subsequent training shall follow Site change control Standard Operating Procedures (SOP).

Commercial Production Equipment used to Manufacture Clinical Batches or Lots, or research equipment used to make commercial APIs and intermediates, must be verified as clean by visual and residue testing after the clinical production.

Approved Cleaning and Sanitizing Materials shall be used to clean product contact equipment and shall be compatible with the surfaces to be cleaned. These materials shall be purchased, received, stored, approved, dispensed, and transferred similarly to raw materials (RM).

For Multi-Purpose Equipment, cleaning, use, and maintenance logs, consisting of chronological entries on sequentially numbered pages or equivalent validated electronic system, shall be maintained for each major Equipment Unit and major Equipment Item that is not included in a defined unit.

Information to be recorded shall include, and not be limited to, the following:

* Documentation of cleaning, use, and maintenance;

* Date of the activity;

* Start and finish times of the activity;

* Equipment use, including product name, as well as initial and final Lot Numbers or Batch Numbers, of a campaign;

* Signature or initials of individual recording the work; and

* Signature or initials of a second person verifying the work, where no other primary Records are in place to document the work.

For non-electronic based equipment cleaning, use and maintenance logs, the issuance, revision, retention and reconciliation of pages must follow Site procedural control as per primary records, such as batch records.

If equipment is dedicated to manufacturing one intermediate or API, individual equipment records are not necessary if batches of the intermediate or API follow in traceable sequence. In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use can be part of the batch record or maintained separately.

For Each Major Equipment Unit, Cleanliness Status shall be indicated, promptly, using either labels and/or signs or a centralized paper-based or validated electronic system. The cleaning status can only be changed to ‘clean’ once all monitoring results are obtained and found to be satisfactory. Examples of equipment cleaning status include, and are not limited to:

*           Hold for Cleaning,

*           Cleaning, and

*           Clean.

Measures to Protect Cleaned Equipment from environmental or microbial contamination during storage must be taken. For example:

 *      Equipment shall not be stored water-wet;

*      Tank openings shall be closed;

*      Open flanges shall be capped or covered; and

*      Portable equipment shall be isolated from environmental exposure by sealing in a protective bag or protected from environmental exposure by shrouding or storage in a clean location.

Cleaned Portable Equipment must be stored segregated from in-use and/or unclean equipment.

Pre-Use Inspections shall be performed immediately prior to use following a changeover cleaning or dedicated equipment campaign cleaning, and documented (e.g., in the next batch or campaign record). Pre-use inspection shall verify that the equipment:

*           Has been properly assembled;

*           Has been cleaned;

*         Is visibly clean;

*           All identification from the prior product has been removed;

*         The cleaning records are complete; and

*          If applicable, analytical results are satisfactory.

For equipment cleaning procedures that require validation, the Site Quality Team must approve the executed cleaning records prior to the disposition of any batch of the next campaign.

Maximum Allowable Time Intervals between use and initiation of cleaning shall be specified, unless there is an approved documented rationale or data demonstrating the time interval is non-critical. These intervals shall include consideration of the variables that could affect cleaning.

After Completion of any Maintenance or Instrument Calibration Activities that required opening or disassembly of product contact equipment; an evaluation must be conducted and documented to determine the level of cleaning required, if any.

Failures During Routine Monitoring (i.e., visual and/or analytical result failures) following changeover cleaning must be documented and Investigated according to established Site SOPs. An evaluation of the impact on validation must be included.

Prior to Being Put into Service, New Major Product Contact Equipment shall be cleaned and verified as visually clean at a minimum. The cleaning and verification of cleanliness must be documented. All new product contact equipment (major and minor) must be visually inspected, if possible, prior to service to ensure that no debris or residue remains. Site Quality Team shall approve the approach to cleaning and verification of new major product contact equipment at the Site.

D. Calibration

This section of practice document establishes the requirements for the Calibration of equipment, instruments, and standards used in Production, storage and testing that may affect the identity, strength, quality, or purity of Pharmaceutical or Animal Health Drug Products, Active Pharmaceutical Ingredients (API),and Medical Devices.

This document applies to all GMP sites and operations and Logistics Centres responsible for production, control, and distribution of Pharmaceutical and

Animal Health drug products, API and medical devices.

Calibration Program(s) shall be established and maintained in all gmp sites defining the responsibilities, criteria, and documentation requirements for the calibration of equipment and instruments used at that Site.

Standard Operating Procedures (SOP) for the Calibration of Each Type of Instrument (e.g., pressure gauge, thermometer, flow meter) shall be reviewed and Approved by technical expert(s) (e.g., System Owner, Responsible Department Head, Engineering and/or Maintenance principals) to ensure that the SOPs are technically correct and approved by the Site Quality Team to ensure that the SOPs are in compliance with applicable regulatory requirements and site quality standards. Environmental, Health, and Safety principals shall be consulted, if required.

The Site Quality Team is responsible for, and not limited to, the following:

*           Approval of calibration SOPs and instrument Specifications;

*           Approval of changes to calibration SOPs and instrument  specifications;

*            Approvals of contractors performing calibration;

*           Assessment of the impact of Out-of-Tolerance calibration results on product quality;

*           Assurance that calibration-related Investigations are completed;

*         Review and approval of all calibration-related investigations; and

*          Approval of changes to instruments or equipment calibration frequencies.

Trained and Qualified Personnel shall perform all calibrations. Records of the training for site colleagues performing calibrations shall be maintained

Instrument Specifications shall be established prior to defining the calibration method for the instrument and shall be based on the requirements of the application and specific parameter(s) that the instrument is intended to measure.

A Unique Instrument Identification shall be assigned to all instruments, including standards, in the calibration program to provide traceability for the instrument. The identifier shall be assigned and the instrument calibrated prior to initial use.

System shall be established to identify instruments which do not require calibration. The rationale for such a determination shall be documented. Instrument Classification (e.g., critical, non-critical, major, minor), based on the potential impact to the process or product if the instrument or equipment malfunctions or is out-of-tolerance, shall be assigned by:

* System Owner, and

* Site Quality Team.

Principals from Engineering, Maintenance and Environmental, Health, and Safety shall be consulted, if required. List(s) of all Instruments Requiring Calibration shall be maintained current at each Site. The list(s) shall include, and is not limited to:

* Instrument identification,

* Instrument classification,

* Instrument location,

* Identification of relevant calibration SOPs, and

* Calibration frequency. Historical Records shall be maintained for each instrument that requires calibration as defined in the Site’s calibration procedures.

System shall be established and maintained at each site to assure the calibration status of equipment and instruments are readily identified with the due date of the next calibration. Calibration Frequencies shall be established for each instrument and shall be based on consideration of, and not limited to, the following:

* Instrument classification,

* Historical accuracy and precision of the specific instrument,

*  Instrument manufacturer’s recommendations,

*  Environmental conditions to which instrument is exposed, and

* Frequency and type of use. Calibration Standards shall be either Primary Standards or Transfer Standards and must be traceable to national or international recognized standards. If national or international standards are not practical or available, an independent, reproducible standard shall be used. If no applicable standard exists, an in-house standard shall be established and maintained at the Site. Certificates attesting to the traceability shall be maintained. Calibration Records shall be maintained for all instruments in the calibration program(s) at the Site and shall be retained according to Site record retention procedures. Defective Instruments or Instruments that Cannot be Brought into Tolerance must be designated as such and taken out of service (e.g., not used and/or removed from work areas).

A Site Change Control SOP shall be followed for, and not limited to, the following:

–           When an instrument is modified or replaced;

–           Changes in instrument calibration frequency;

–           Changes in instrument tolerances;

–           Location or environmental change for stationary equipment;

Changes in process Normal Operating Ranges (NOR) that affect the calibration of instruments. Computerized Systems used to maintain calibration records must be Validated .

Prior to Removing an Instrument from Service, a final calibration shall be performed, if possible (i.e., instrument is still functional), to Verify that the instrument is still within tolerances.

An Investigation shall be performed and documented and both the Site Quality Team and the responsible System Owner shall be notified if an instrument is found to be out-of-tolerance or beyond the calibration due date and is subsequently used beyond the due date.

Recalibration of an Instrument shall be performed if an instrument is subjected to a condition that could adversely impact its calibration or operation (e.g., dropped or damaged). Stationary instruments shall be recalibrated before and after movement.

Environmental Factors that May Affect Measurements or Calibration shall be identified, controlled, or monitored, and records maintained. Calibration Equipment, including standards, must be safe to operate in the specific process area in which the equipment is being used. When calibration equipment is used in multipurpose facilities, steps must be taken to prevent Cross Contamination.

Contractors Performing Calibration shall have systems and procedures in place equivalent to those described in this practice document or follow site SOPs. For Contract Vendors, the responsible Site Quality Team shall assure that the methods, facilities, and controls used by the contract vendor are, at least, equivalent to those of the sponsoring site. If a Calibration Service Contractor is used the following must be maintained at the Site using such services:

* Name and address of contractor;

* Documentation of the qualifications of person performing calibrations; and

* Documentation of services performed.

E. Preventative Maintenance

This section of practice document establishes the requirements for Preventive Maintenance (PM)of Direct Impact Systems and associated Critical Components used in Production, storage, and testing that may affect the safety, identity, strength, quality, or purity of Active Pharmaceutical Ingredients (API), Drug Products, Drug Product Raw Materials (RM),API Starting Materials, Critical In-Process Materials, Critical Intermediates, Biologics or Medical Devices.

PM of components on Indirect Impact Systems, No Impact Systems or Non-Critical PM Tasks on Direct Impact Systems and associated Critical Components are outside of the scope of this document.

Laboratory testing equipment is also included within the scope of this document.

Calibration activities are outside the scope of this document.

This document applies to all gmp Production Sites and Logistics Centers responsible for the production, testing, storage, and distribution of Pharmaceutical or Animal Health APIs, intermediates subsequent to the API starting material, drug products, medical devices, or biologics.

A PM Program shall be documented and approved in a Site Standard Operating Procedure (SOP). The PM Program shall define the responsibilities, criteria, and documentation requirements for work performed and shall follow the Site requirements for review and approval.

The SOP shall be reviewed and Approved by the System Owner, the Site Quality Team and Engineering/Maintenance or the Business Unit responsible for PM.

PM Task shall be considered critical unless there is documented rationale to support it as non-critical. Such documentation shall be approved by the System Owner and the Site Quality Team.

System shall be established to identify laboratory systems or Direct Impact Systems and associated Critical Components that are within the scope of this document, but do not require PM. The rationale for such determination shall be documented.

System Owners shall ensure that systems and associated components that require PM are identified and entered into the PM Program in accordance with Validation and change control requirements. Documentation Providing Instructions (e.g., Written Instructions) for the PM of Individual Systems and Associated Components shall be reviewed and approved as defined in the Site PM Program including review and approval by technical expert(s) (e.g., System Owner, Engineering/Maintenance or the Business Unit responsible for PM).

Lists of Systems and Associated Components Requiring PM shall be maintained at each site as part of the PM program. Each component requiring PM shall be uniquely identified.

System shall be established for the management and control of replacement parts and materials used during PM activities Systems and Associated Components that have Undergone PM that resulted in disassembly and reassembly or that have otherwise potentially affected the cleanliness of direct Product Contact Equipment shall be evaluated by the System Owner to determine the level of cleaning required prior to use.

The Documented Instruction(s) for PM Activities and Requirements (e.g., PM Job Plan) shall serve as the basis for creation of individual PM instructions (e.g., PM Work Orders).

When documented instruction(s) for PM activities and requirements (e.g., PM Job Plan) are changed or developed, it shall be evaluated and approved as defined in the Site PM Program including evaluation and approval by the System Owner, Engineering/Maintenance or the Business Unit responsible for PM. PM Requiring Inspections shall include defined acceptance criteria that can be used to determine if the system and associated components pass or fail the inspection. Acceptance criteria and the rationale shall be documented.

New or Modified PM Acceptance Criteria that impact the safety, identity, strength, or quality of the product (e.g., validation and/or regulatory commitments) shall be approved by the System Owner and the Site Quality Team.

An Investigation shall be performed and documented in a Deviation report if a Critical PM Task is found to be beyond the scheduled frequency and/or outside of the acceptance criteria for the PM activity and the system and associated components are subsequently used.

The Site Quality Team and the System Owner shall be notified of such events. The documentation shall include Impact Assessments on Batches or Lots produced using the system and associated components under investigation. The System Owner shall:

* Investigate additional PM work performed beyond that which is detailed on the individual PM instructions (i.e., PM Work Order);

* Initiate a deviation report if the investigation determines that there is potential impact to product quality; and

* Review and document the Verification that the PM was completed prior to returning the systems and associated components back into service. Defective Systems and Associated Components shall be removed from the location of use (e.g., Production Area), if possible, or at a minimum, designated as defective and out-of-service.

PM Records shall be current and readily retrievable and shall be maintained in accordance with the Site record retention SOPs.

Computerized Systems used to schedule or track PM, and/or to maintain PM records must be validated. Equipment Documentation (i.e., System Cleaning, Maintenance, and Use Records) resulting from PM shall be recorded.

PM Activities shall be performed and maintained by Qualified personnel. Records of training shall be maintained.

On-Site PM Performed by Qualified Contractors or Vendors shall comply with this document.

F. Cleaning and Sterilization of Aseptic Manufacturing Equipment

Equipment Used in Aseptic Processing shall be designed to minimize the risk of particulate and microbiological contamination. Design considerations for such equipment shall include, and are not limited to, the following:

* Sanitary fittings for all pipe and hose connections;

* Materials of construction that allow repeated cleaning and Disinfection treatments;

* Avoidance of crevices, occluded surfaces, and hard to clean areas;

* Product contact surfaces resistant to rusting, pitting, corrosion, and peeling; and

* Ease of assembly and disassembly.

This practice document applies to all GMP sites and operations where Sterile Active Pharmaceutical Ingredients (API), sterile Drug Products, and sterile Medical Devices are produced for Pharmaceutical and Animal Health.

Equipment Used in the Manufacture, Holding, Sampling, and Processing of sterile APIs, sterile drug products and aseptically processed sterile medical devices shall be cleaned and sterilized following written and Approved Standard Operating Procedures (SOP) and a Validated Process.

Equipment that Contacts Sterile APIs, Sterile Drug Products, Sterile Medical Devices, Sterile Raw Materials (RM) and Sterile Components (e.g., Containers and Closures) shall be cleaned and stored in a manner designed to prevent microbial, Bacterial Endotoxin and Foreign Matter contamination.

Equipment that is cleaned with water shall be washed and rinsed using water with appropriate quality. The final rinse must be with non-recycled Water for Injection (WFI).

Personnel shall be Qualified to perform activities related to:

*           Equipment cleaning;

*           Preparation of equipment for Sterilization;

*           Sterilization of equipment; and

*          Handling of sterile equipment.

Equipment shall be cleaned within a specified period of time after use and shall be thoroughly dried before storage.

The Initial Cleaning of Equipment to Remove Gross Soil shall be performed in an area with the applicable Air Classification.

Personnel performing the initial cleaning shall wear the following:

 *          Plant issue Uniform and shoes;

*          A second layer of plant issued clothing or disposable covering;

*           Eye protection as required; and

*           Head and beard covers.

Final Rinsing of Equipment shall be performed in an area with the applicable air classification. Personnel performing the final rinsing of equipment shall follow the Preparation for Aseptic Areas (PAA) gowning practices. In addition to the PAA gowning requirements, additional equipment, dedicated to the area, may be worn if required for safety purposes.

Clean Equipment shall be handled in a manner designed to prevent contamination and shall be prepared for sterilization in an area with the applicable air classification that is separated from the equipment final rinsing area. Personnel preparing equipment for sterilization shall follow PAA gowning practices.

New or Purchased Wrappings for Sterilization (e.g., autoclave bags, biowrap) must meet the following requirements:

 *          Defined by Specifications;

*           Supplied by an Approved Supplier;

*          Inspected upon receipt; and

*           Inspected for cleanliness and integrity prior to use. Any wrappings failing inspection shall not be used.

Disposable Sterilization Wraps shall be used, if possible. If reusable wrappings are used, studies shall be conducted to demonstrate the number of times reusable wrappings can be cleaned and sterilized before discarding, and a system for tracking the number of cleanings and sterilizations shall be implemented.

Sterilized Equipment shall be protected from recontamination by such means as wrapping the equipment prior to sterilization in non-shedding material that is permeable to the Sterilant, or covering the equipment with a metal cover placed in a container that will not trap air or retain condensate during Steam Sterilization. Aluminum foil shall not be used.

Washing Bays and Equipment Washing Machines or Cabinets shall be designed and maintained to minimize microbiological, particulate, and bacterial endotoxin contamination.

Clean-In-Place (CIP) Systems shall be designed to assure the cleaning of all equipment internal surfaces. Features that interfere with cleaning (e.g., Dead-Legs, poor spray ball coverage) must be avoided.

Sterilization Processes for Equipment that directly contacts or has the potential to contact sterile APIs, sterile drug products, sterile medical devices, sterile RMs, or sterile components shall be Validated using an Overkill Sterilization method.

Clean Steam shall be used in Production steam sterilization processes, shall be routinely tested, and shall meet specifications for chemical and biological attributes.

CIP and Steam-In-Place (SIP) Systems shall include, and not be limited to, the following design considerations:

 *          Polished or electropolished 316L stainless steel sanitary piping, fittings, valves, instrumentation, and steam traps;

*           Piping system pitched downward to drainage points; and

*          Calibrated Instruments and Elements (I/E) for continuous monitoring of Critical Process Parameter values, such as temperature, pressure, fluid levels, and fluid flow.

Sterile Gas (air or nitrogen) shall be used to pressurize the system after completion of SIP to:

*           Blow the final condensate through traps; and

*         Maintain the sterilization integrity of the equipment. Positive gas pressure shall be confirmed prior to equipment use.

Preventive Maintenance (PM) of CIP/SIP Systems shall be performed at specified intervals, not to exceed annually.

–           Sterile Equipment shall be delivered to the Aseptic Processing Area (APA) in a manner designed to prevent contamination, such as through double-sided Batch sterilizers or Airlocks.

–           The Maximum Time Interval Between Washing and Sterilization of equipment must be established and validated if the equipment is not stored under protected conditions. The maximum time interval between sterilization and use of equipment shall be validated.

Measures to Differentiate sterile equipment from non-sterile equipment shall be defined. Examples of these measures include:

 *         Supplier identification of sterile items;

*          Sterilization indicators;

*           Facility design (e.g., material flow patterns); and

*           SOPs for handling equipment before and after sterilization (e.g., material separation).

Each Carrier (e.g., Cart, Basket, Tray, or Plastic Bag with Breather Panel) of Equipment and Individually Wrapped Equipment readied for sterilization shall be identified (e.g., with a non-shedding label such as Tyvek or metal tag) with the following information:

*           Identification of person preparing the equipment for sterilization;

*           Description of the equipment or item;

*           Sterilizer identification;

*          Specified sterilization cycle identification;

*          Date of sterilization; and

*           Expiration Date.

Wrapped Equipment Sterilized in a Batch Sterilizer shall be unloaded and stored in an environment with the applicable air classification for a period of time not to exceed the maximum specified validated time interval.

Sterilized Equipment shall be visually inspected for damage to the wrapping prior to storage or use. Damaged packages shall be labeled as damaged and removed from the APA.

Equipment Cleaning and Sterilization shall be documented and included in batch /Lot Records.

G. Areas and Facilities Cleaning and Maintenance

This section of practice document defines the cleaning and maintenance of GMP facilities (e.g., rooms/areas, modules) used in the Production, Sampling, or Subdivision of Drug Product Raw Materials (RM), Intermediates (post-introduction of the API Starting Material), drug product In-Process Materials, Active Pharmaceutical Ingredients (API), drug products, Packaging Materials, Biologics, or Medical Devices. Such areas or facilities shall be cleaned and maintained in ways that:

* Ensure personnel safety;

* Ensure levels of cleanliness and sanitation that are consistent with operations in each area and compatible with control measures;

* Protect processes, Production Materials, and products from microbial and other contamination; and

* Provide a Visibly Clean, well maintained, and organized work area throughout the Site.

This practice document applies to GMP sites responsible for production, sampling, and sub-division of drug product raw materials, packaging materials, intermediates (post-introduction of the API starting material), APIs, drug product in-process materials, drug products, biologicals, or medical devices.

Cleaning and Maintenance Activities shall not affect product quality or result in Cross Contamination or microbiological contamination of products or materials.

Cleaning Activities in Production Areas shall be performed by Qualified personnel following written Standard Operating Procedures (SOPs)that are Approved by the Site Production Team and the Site Quality Team before being issued. Cleaning SOPs shall include or reference, but are not limited to, the following:

*           Cleaning schedules;

*         Detailed descriptions of methods, tools, and materials used in area cleaning; and

*           Means of protecting clean areas from contamination prior to use.

Cleaning and Maintenance Activities in Production Areas shall be documented at the time of performance and the Records retained according to Site record retention procedures.

Cleaning and Maintenance Measures in Production Areas shall include, and are not limited to, the following:

 *          Processing areas cleaned at defined frequencies;

*           Drains in processing areas cleaned and sanitized as applicable, at pre-determined frequencies;

*           Production equipment is cleaned at established intervals, and

*           Cleaning and maintenance SOPs.

Cleaning of Production Areas where there is open product exposure shall include, and not be limited to, the following types of cleaning:

*           Changeover Cleaning;

*           Interval Cleaning during a Campaign as necessary (e.g., after maintenance); or

*           Dedicated Area or Module Campaign Cleaning.

Where There is Open Product Exposure, the Need for Production Area Cleaning, Type or Level of Cleaning, and Cleaning Frequency Within a Campaign shall be defined and documented.

Where There is Open Product Exposure, a Qualified Individual other than the one who performed the cleaning must Verify that an area or module is visibly clean.

For Production Areas Where There is Open Product Exposure, Pre-Use Inspections shall be performed immediately prior to use following a changeover cleaning and/or Dedicated Equipment Campaign Cleaning. The pre-use inspection shall be documented in the Batch/campaign record of the next Lot/batch to be processed in the production module or area, or in the room/area log-book or SOP checklist. Pre-use inspection shall verify:

*           Area or module has been cleaned, including production equipment in the area or module;

*           Area or module is visibly clean;

*           Containers, Closures, Labels, production materials, product, documentation and identification from the prior batch/lot have been removed;

*           Cleaning records are complete; and

*           If applicable, analytical results are satisfactory.

Cleaning and Sanitizing Agents Used in Production Areas shall be compatible with the surfaces to be cleaned. Preparation of bulk cleaning or sanitizing agents, if used, shall be described in a written and approved SOP.

These materials shall be purchased, received, stored and approved in a controlled manner (e.g., from a pre-Approved Supplier as raw materials) and dispensed and transferred to production in the same manner as raw materials.

Dust Collection Filters on Return Air System in Production Modules Where Products (Drug Products, Final APIs, Medical Devices) are Exposed shall be replaced when changing from one product to another unless otherwise justified in a documented Risk Assessment. For dedicated (i.e., single-product) modules, the filters shall be replaced at established frequencies (e.g., after several batch/lots). Filter replacement shall be documented.

Production Areas shall be inspected at a defined frequency for the need for maintenance and/or cleaning. This shall include at least the following:

*          Peeling or flaking paint,

*         Broken or defective equipment,

*           Accumulation of dust or debris,

*           Defective or broken seals and/or screens on doors and windows,

*           Leaking pipes,

*          Stagnant water, and

*           Facility integrity (e.g., cracks or holes in walls).

Corrective actions shall be taken as soon as possible upon discovery of these items.

Contractors Involved in Cleaning and Maintenance Activities in Production Areas shall be qualified and subject to the requirements of this practice.

H. Pest Control

This section of practice document defines the Pest control requirements for buildings and facilities at GMP sites and Logistics Centers that are used for Production, testing, or storage of the following:

* Raw Materials (RM),

* Starting Materials,

* In-Process Materials,

* Intermediates,

* Active Pharmaceutical Ingredients (API),

* Drug Products,

* Over-The-Counter (OTC) Products,

* Cosmetic products,

* Biologics,or

* Medical Devices.

A Pest Control Program shall be implemented and maintained at each GMP Production Site and Logistic Center. The program must be designed to protect against entry and harboring of pests. Responsibility for maintaining the Pest Control Program shall be assigned to a Qualified Site Pest Control Coordinator.

Pest Control Practices are to be described in current and available written procedures Approved by the Site Quality Team , including any Standard Operating Procedures (SOP) used at the Site by the contractor.

Buildings and Premises shall be designed and maintained to protect against the entry and harboring of pests.

Measures for Safe and Proper Use of Pest Control Chemicals shall be included in the Pest Control Program.

Pest Control Chemicals shall be used only if the Site has written evidence that the chemicals are registered by government Team and used according to local, state, and national laws covering the use of pest control chemicals. The registration documentation for the pest control chemicals may be maintained at the pest control contractor location, but Site principals must assure that the documents exist before allowing the pest control contractor to use the chemicals at the Site.

The Site Quality Team is responsible for approval of a Site-specific program for:

*           Inspection of rodent traps inside buildings used for production, testing, and/or storage and outside such buildings; and

*           Inspection, emptying and cleaning of bug lights.

Pest Control Contractor Agreements must be in place at all Sites using pest control contractors.

Locations of Permanent Pest Control Devices (e.g., rodent bait traps, mechanical non-bait traps, insect bug lights) shall be identified by permanent signs and indicated on detailed area maps. Locations of monitoring devices (e.g., sticky traps) to assess activity are not required on the detailed area maps, but such devices shall be inspected, accounted for, and documented.

Rodent bait shall only be used indoors if approved by the Site Quality Team. Rodent bait may be used outdoors.

Food, Beverages, and Plants are prohibited from areas (e.g., rooms, modules) used for production, testing, and/or storage of items.

Buildings used for production, testing, and/or storage of items shall be inspected at least annually to minimize the potential for pest ingress.

I. Water Purification, Storage, and Distribution for Pharmaceutical Production

This section of the practice document defines the requirements for the purification, storage and distribution of water used for Production including water used for cleaning of Product Contact Equipment, Containers, and Closures.

This document applies to GMP production sites and operations where the production activities are performed for Pharmaceutical or Animal Health Drug Products, Active Pharmaceutical Ingredients (API)and Medical Devices.

Water Quality Criteria for Use in Production must take into account the stage of production, intended use of the water, and the end product requirements.

Design of Purified Water (PW), Highly Purified Water (HPW) and Water for Injection (WFI)Systems shall include:

* Sanitary distribution piping and sanitary storage vessels;

* Smooth and sanitizable interior surfaces;

*Continuous circulation distribution systems;

* In-line, continuous monitoring Instruments and Elements (I/E) to detect system failures;

* Procedures for continuous or intermittent sanitizing;

* Drainable distribution piping and storage vessels;

* Piping sloped to allow for complete drainage of storage tank and distribution system;

* Minimizing the number and length of Dead-Legs;

* Backflow prevention, which protects the water system from contamination;

* Sample ports after each water-processing stage;

* Sanitary valve connections;

* Exclusion of threaded connections;

* Clean, smooth finished welded joints; and

* Installed gaskets that match the pipe diameter.

Alternate designs are allowed (including stand-alone and portable purification units) for Reduced Ion Water, Deionized Water, Low Microbial Deionized Water and Low Endotoxin Deionized Water Systems used in API manufacturing provided they are Validated.

Design and Validation of WFI Systems shall include Specifications and sampling plans for feed water, which minimally address seasonal variation, and purification of feed water beyond potable water standards. Specifications and sampling plans for WFI feed water shall be justified and documented.

All Water Systems Used in the Manufacturing of APIs, Drug Products, and Medical Devices, where the water is purified beyond Potable Water quality,  must be validated and monitored. In addition, validation of Low Endotoxin Deionized Water, HPW and WFI shall include Bacterial Endotoxin removal steps.

Hydrophilic Microbial Retentive Filters shall not be used in water storage and distribution systems. If point of use filters are used, they shall not be permanently installed and must be replaced after each Batch or Lot.

Passivation of stainless steel water generation, storage, and distribution systems, except potable water systems, and the subsequent cleaning and testing shall be performed before initial system startup and after major repairs, to minimize corrosion of metal surfaces and to maintain water quality. An inspection of the system shall be periodically performed (e.g., every two years) to detect severe Rouge (i.e., rouge deposits widely distributed in the system based on inspection of piping and gaskets) and/or pitting. The inspection frequency shall be established at the Site based on the analysis of historical data. The system shall be passivated if the inspection indicates the need for passivation.

Water Used in Equipment Cleaning, Final Rinse, and Manufacturing for API or drug products shall be in accordance with the water types shown in Tables 1 and 2.

Water Quality Maintenance Measures shall include, at least, the following:

* Monitor potable water;

* Monitor water purification processes (e.g., deionizers) periodically to obtain a microbial profile of the water system;

* Validate and maintain water treatment, storage, and distribution systems;

* Monitor and maintain Conductivity within specified Normal Operating Ranges (NOR);

* Monitor water quality by physical, chemical, and microbiological tests;

* Continuously or periodically sanitize water storage and distribution systems, as applicable to grade of water;

* Remove and drain hoses after use;

* Repair leaks;

* Integrity Test vent filters on still condensers and storage tanks before and after use;

* Integrity test heat exchangers at least annually, unless data support a longer interval; and

* Routinely calibrate in-line monitoring equipment.

A Documented and Approved Monitoring Program for all types of water shall be established and include, at least, the following:

*           Frequency of sampling and testing;

*           Acceptance criteria (e.g., Alert Levels, Action Levels, and specifications) for physical, chemical, and microbiological attributes, as applicable to the intended use of the water;

Compendial grade water shall be tested for conformance with applicable compendial requirements (e.g., EP, JP, USP);

*           Deionized water grades shall be tested for conductivity and Total Organic Carbon (TOC) using applicable compendial test methods;

*          Minimal testing for PW shall be TOC, conductivity, and microorganism counts;

*           Minimal testing for HPW and WFI shall be all tests required for PW plus Bacterial Endotoxin Testing (BET);

*           Documentation and review of water monitoring results, that include Trending; and

*           Documented Investigations, including corrective actions, when acceptance criteria are exceeded.

Materials with Direct and Potential Contact with Water Purification, Storage, and Distribution Systems, such as passivation chemicals and resins, shall be approved by the Site Quality Team . Release requirements shall be defined by specifications. Additionally, the materials of construction of the gasket and its suitability for use in the water system shall be reviewed to ensure compatibility with the water system.

Dedicated Resins shall be required when using contract resin services. Site Quality Auditors shall review vendor Standard Operating Procedures (SOP) and resin practices during the vendor audit to ensure compliance with this policy.

Storage and Distribution Systems for Reduced Ion and Deionized Water shall include:

* A complete distribution system newly installed shall be a continuous circulation loop;

* Legacy Systems with one-way distribution systems shall have regular flushing (based on validated intervals) of lines and/or sanitization (e.g., chlorination, heat, ozonation) to provide microbial control. (Note: Deionized Water systems shall not be chlorinated as by definition the water would not meet the requirements for conductivity);

* Piping from water distribution systems to manifolds and process vessels shall provide drainage following use or shall be blown dry with filtered nitrogen or air;

*  A bottom drain in storage tanks for drainage and cleaning;

* Air breaks in drain piping; and

* Positive pressure in distribution system.

Storage and Distribution Systems for PW shall include:

 *          Low carbon stainless steel (316L) or plastic storage vessels and piping;

*          Sanitary valves, pumps, and fittings;

*           Re-circulating distribution loops;

*           Means to minimize microbial contamination, such as Ultraviolet (UV) lights, heat treatment, or ozone injection;

*           Water return through a spray ball located in the storage tank headspace, except for systems that are ozonated or systems that are operated continuously hot;

*           A bottom drain in storage tanks for drainage and cleaning;

*           Vented tanks protected with Hydrophobic microbial-retentive filters designed to be condensate free (e.g., heated housings);

*           Tanks using a pressurized headspace in lieu of Vent Filters must be pressurized with a pharmaceutical grade gas (e.g., air or nitrogen) that has been filtered through a hydrophobic, microbial-retentive filter. Tank head pressure must be controlled;

*           Air breaks in drain piping; and

*           Positive pressure in distribution systems.

In Addition to the PW System Design Requirements, Storage and Distribution Systems for HPW and WFI shall include:

*           Polished (e.g., 25 Ra micro inch or 0.64 Ra micron) or electropolished 316L stainless steel tank finish and sanitary piping with 3-A sanitary clamp-type fittings or equivalent; and

*           Double tube sheet heat exchangers and in addition, energy economizing heat exchangers meeting sanitary design standards that contain the same pharmaceutical grade water on both the utility and process sides of the heat exchanger may be used.

Water Systems employing the use of ozone shall include inactivation of the ozone prior to using the water in manufacturing. Testing shall demonstrate that residual ozone levels are below established acceptable levels prior to use of the water system. Materials used in gaskets, in-line monitoring equipment, and sanitary valves shall be compatible with ozone when it is used in the water system.

Water System Sanitization, for systems that are not self-sanitizing, shall be performed with hot (e.g., > 80o C) water, steam, oxidizing chemicals, regeneration chemicals, or passivating chemicals following a validated method. Testing shall demonstrate that residual levels of any chemicals used for sanitization are below established acceptable levels prior to use of the water system. Sanitization shall be performed at validated intervals.

Water Samples at Points of Use shall be collected in a manner consistent with manufacturing practices. Flushing of sample ports shall be the same as for manufacturing use of the water at corresponding use points.

Water Samples for Microbiological Tests shall be collected in Sterile containers using a technique designed to minimize microbial contamination of the samples. Microbiological testing shall be conducted as soon as possible after collection. If samples cannot be processed within 8 hours of sample collection, the samples shall be refrigerated at a temperature of 2 to 8o C. The time between collection and testing shall be recorded and shall not exceed 24 hours.

Water Samples shall be identified to include, at least, the following:

*           Date;

*           Time;

*          Type of sample (e.g., Potable, Deionized, WFI, PW);

*          Sample location identification; and

*           Identification of person taking sample.

Identification of Microbial Isolates shall be performed as follows:

* During the first year of water system operation, representative distinct microbial isolates should be characterized (e.g., gram stain, cellular and colonial morphology) and identified to the genus and species level, if possible;

* If Objectionable Microorganisms are not present in the normal microbial flora of the water system, then identification of microbial isolates is only required when alert or action levels are exceeded; and

* For legacy systems where the normal water system microbial flora have not been characterized, the characterization and identification of water system flora shall be conducted as determined by documented Risk Assessment.

The Water System and the Potable Water Feed to the Water System shall be sampled and tested for the objectionable microorganisms, including and not limited to the following:

*           Coliforms;

*           Any additional objectionable microorganisms identified in applicable drinking water regulations;

*           For PW, HPW, or WFI used for drug product manufacturing, any objectionable microorganisms identified for the drug product dosage form; and

*           Where the water is used in final API manufacturing steps, any objectionable microorganisms identified for the drug product dosage form for which the API is intended.

If data demonstrate that objectionable microorganisms are not part of the normal water system microbial flora, routine testing for objectionable microorganisms is not required. If objectionable microorganisms are found in the water system, an investigation must be performed and corrective action taken to eliminate the objectionable microorganisms from the water system.

Water Used in the Final Isolation and Purification Steps for Non-Sterile APIs that are intended for sterile drug products shall be monitored and controlled for total microbial counts, objectionable organisms, and endotoxins where required (e.g., for Parenteral products).

Water used in the Final Steps for Sterile APIs and Sterile Drug Products must be rendered sterile, if there are no further Sterilization steps in the process.

Table 1: Water Use Requirements for Active Pharmaceutical Ingredients (APIs)

 Table 2: Water Use Requirements for Drug Products

For Products Manufactured in or for Canada, WFI shall be sampled daily from at least two points during processing. Sampling of use points shall be on a rotating basis as to cover all use points. Alternative sampling may be performed if supporting documented justification is available at the Site.

J. Air Handling Systems & Air Classifications for Aseptic Operations

Air Handling Systems for Aseptic Environments where the final steps of Sterile Active Pharmaceutical Ingredients (API) Production are performed and sterile Drug Products and aseptically processed sterile Medical Devices are produced shall be designed to provide the required room Air Classifications in order to minimize particulate and microbial contamination of materials being processed in the Aseptic Processing Area (APA).

This practice document applies to GMP Sites where sterile medical devices, sterile drug products, or sterile APIs are produced for Pharmaceutical and/or Animal Health.

Air Handling Systems shall be Commissioned and/or Qualified appropriately.

HVAC Systems for Aseptic Operations shall be designed with terminal High Efficiency Particulate Air (HEPA) Filters. Such HVAC systems shall be installed in a manner that allows for cleaning, maintenance, and control (e.g., air balancing dampers, control sensors) to be performed outside of APA with the following exceptions:

*           When self contained unidirectional airflow hoods exist and are needed within such areas;

*           When performing aerosol challenges and leak testing or replacement of individual HEPA filters with the area in a non-aseptic mode; and

*           When manual air damper controls are located in the area.

HVAC Systems for Aseptic Operations shall be used to supply air under positive pressure to areas with following air classifications:

Figure: Air Classifications

For Classification Purposes in Grade A Zones, a minimum sample volume of 1m3 shall be taken per sample location. Sample volumes of less than 1m3 are acceptable for routine monitoring.

A Pressure Differential of at least 10 pascals [0.04 inches Water Gauge (WG)] shall be maintained between adjacent rooms of different air classifications, and shall be continuously monitored.

A pressure differential of at least 12.5 pascals (0.05 inches WG) shall be maintained between the aseptic processing room and any adjacent unclassified room(s), and shall be continuously monitored.

For Adjacent Rooms of the Same Air Classification that require a pressure differential to be maintained between the rooms (e.g., Lyophilizer filling area to lyophilizer loading area), a minimum pressure differential, sufficient to     ensure airflow in the proper direction, shall be established during commissioning and/or qualification studies (e.g., Smoke Mapping Studies)and shall be monitored.

For Products Requiring Special Containment Measures, such as live biological agents, cytotoxic drugs, sex hormones, and certain highly active drugs, additional measures must be in place to prevent Cross Contamination into other areas (e.g., rooms at negative pressure with respect to adjacent rooms and HEPA filtration of exhaust air).

Smoke Mapping Studies shall be performed during commissioning and/or qualification in Grade A and B processing and filling environments to demonstrate airflow patterns under At Rest and In Operation conditions and to establish airflow velocity at a defined distance proximal to the work surface (e.g., 6 to 12 inches above the work surface) in Grade A environments. Smoke    mapping studies shall include allowed routine manual interventions by personnel including environmental monitoring activities. Smoke mapping studies shall be videotaped. Smoke mapping studies shall be repeated when there are changes including, and not limited to, the following:

*           Installation of additional new HEPA filtration units;

*           Installation of new equipment in Critical Zones;

*           Equipment modifications in critical zones, if the modifications can affect the unidirectional airflow (e.g., air speed change, airflow pattern change); and

*         Changes in manual manipulation of the equipment or operator interventions that affect airflow patterns.

Airflow Velocity at a Defined Distance Proximal to the Work Surface (e.g., 6 to 12 Inches Above the Work Surface) in Grade A Environments shall be routinely monitored at specified monitoring locations. Alert/Action Levels shall be established based on the velocity data obtained from routine monitoring. Initially, the lower limit for the action level shall be within 20 percent of the value determined during smoke mapping for the specified monitoring location. The velocity data shall be evaluated on at least an annual basis and the alert/action levels revised to represent the current monitoring data.

Videotapes of Smoke Mapping Studies shall be treated as Validation data and shall be reviewed and retained as such.

The Integrity of HEPA Filters in the aseptic processing room (i.e., Grades A and B environments) shall be Verified upon installation and at least every 5 to 7 months thereafter by Qualified personnel. The integrity of HEPA filters in Grades B (non-grade A background), C, and D environments shall be verified upon installation and at least once a year thereafter. The verification reports shall be reviewed by the Validation Committee (VC).

Alarm Systems shall be in place to signal and/or record out of rang conditions when specified alert/action level ranges are exceeded for continuously monitored Critical Process Parameters.

Time Limits defining how long the environmental monitoring results can exceed action levels for Total Airborne Particulates, temperature, humidity, or pressure differential shall be established and justified (e.g., during qualification studies). Actions to be taken when such time limits are exceeded, including in the case of a power failure, shall be defined based on risk assessment.

An Environmental Monitoring Report (EMR) shall be completed when environmental conditions exceed specified alert/action ranges. Environmental conditions outside action level ranges require a documented Investigation and corrective action.

Air Handling Systems and Primary Unidirectional Airflow Units shall operate continuously, except when shut down for maintenance. Procedures shall be established for the use and maintenance of these systems and the use and maintenance of secondary unidirectional airflow units.

Design Criteria for Air Handling Systems to control total airborne particulate levels shall take into consideration Displacement System Design and Dilution System Design requirements, and shall include, and not be limited to:

* Establishment of room air classifications (Grade A, B, C, or D) that are required for the activities conducted in these areas;

* Establishment of pressure differentials;

* Automatic monitoring, recording, and alarming of critical process parameters (e.g., temperature, humidity, and pressure differentials); and

* Temperature and humidity within specified limits and not at the dew point.

Air Handling Systems for Grade A Environments shall be designed to provide, and not be limited to, the following:

*        Air supplied through terminal HEPA filters;

*        Maintenance of unidirectional airflow at the work surface sufficient to displace particulates as demonstrated by smoke studies;

*          Minimum airflow velocity, within 6 inches of the filter face, of 72 feet per minute (0.36 m/s) with a maximum airflow velocity that does not exceed the manufacturer’s specified limit; and

*        Airflow velocity at a defined distance proximal to the work surface (e.g., 6 to 12 inches above work surface) within alert/action levels.

Air Handling Systems for Air Classifications in Grade B and Grade C Areas shall include, and not be limited to:

*        Air supplied through terminal HEPA filters;

*        A minimum of 20 air changes/hr; and

*        Air volumes sufficient to maintain the required room air classification and environmental conditions, and to achieve the required Recovery Time (e.g., 15 to 20 minutes) (see EU GMPs Annex 1 – Ref 6).

Airborne Particulates Levels can be decreased by the recirculation of room air through self-contained, HEPA-filtered, unidirectional airflow hoods or secondary unidirectional airflow units. The effect of airflow hoods shall not be used to determine the minimum room air changes for new installations.

Selection Criteria for HEPA Filters shall be verified and documented and shall include, and not be limited to, the following:

*         Physical dimensions;

*         Prefilter provisions;

*          Airflow requirements;

*         Efficiency rating;

*         Materials of construction (Note: wood or wood components shall never be used);

*           Gel seals or properly installed non-shedding gaskets (Note: asbestos gasket material shall never be used);

*           Location and type of ports to permit in-place testing of static pressure and the introduction of aerosol challenge particles; and

*           Manufacturer certification of filter integrity prior to shipment.

Commissioning and/or Qualification of Air Handling Systems shall include but not be limited to, the following:

* Perform HEPA filter Integrity Test;

* Verify that the pressure drop across the HEPA filter meets manufacturer Specifications;

* Conduct and videotape smoke mapping studies under “At Rest” and “In Operation” conditions using simulated operations in the vicinity of critical work areas and equipment;

* Establish alert/action levels for airflow velocity at a defined distance proximal to the work surface (e.g., 6 to 12 inches above the work surface) for Grade A environments;

* Identify and correct vortices or turbulent zones to ensure airflow is sweeping away from the work surface;

* Confirm pressure differentials, humidity, and room air changes;

* Establish recovery time to return to “At Rest” air classification specifications after operations or interruption to the air supply (e.g., power outage).

Measure total airborne particulate of the area laid out in a grid pattern, under “At Rest” and “In Operation” conditions;

Perform microbiological environmental monitoring under “At Rest” and “In Operation” conditions;

Analyze the data to confirm that the area meets the designated air classification; and

Select routine monitoring sites based upon the worst sites determined during commissioning and/or qualification.

Smoke Map Studies shall be visually recorded to a durable medium (e.g., videotape) and supported by a written narrative with specific conclusions. The written narrative shall be prepared following the execution of the smoke mapping studies and shall include the test data, notes, and conclusions. Voice over or other sounds are not required to be on the visual recording. The visual recording shall not be altered or edited, but the recording can be started and stopped as required during testing. The visual recording will serve as support to the written narrative. The visual recording shall be labeled with the Protocol number and title and protected to ensure it is “read-only.” All observations made during the smoke mapping study of suspect equipment, personnel, or air pattern concerns shall be documented.

An Acceptable Smoke Mapping Study shall meet the following minimum criteria:

*           The critical work surface is bathed in HEPA-filtered air;

*           There are no stagnant zones in the critical work area; and

*           There is no entrainment of lower quality air into the critical area.

Air Handling Systems shall meet the performance criteria defined in Table 1 upon installation and during their entire use.

Standard Temperature HEPA Filters shall be verified for integrity and pressure drop across the filter, and airflow velocity as follows:

* Challenge particles introduced into the upstream side of the HEPA filter (e.g., 4CSTPAO introduced as a polydispersed aerosol having an approximate mean diameter of 0.3 micron size at a concentration of 10-90 micrograms per liter of air);

* The entire HEPA filter surface and frame for accessible filters shall be scanned downstream for leaks [e.g., using a photometer probe at a scanning rate of no more than 5 cm/sec (2 inches/sec) at a distance of 2.5 cm (1 inch) from the filter face];

* Any single probe reading greater than the applicable limit shall be indicative of a significant leak and shall require either repair or replacement of the HEPA filter (e.g., a reading equivalent to 0.01 percent of the upstream challenge when performing the leakage scan test using a photometer);

* Airflow velocities shall be measured 6 inches from the filter face. Airflow velocity for HEPA filters in Grade A shall be a minimum of 72 feet per minute (0.36 m/s), and shall not exceed manufacturer’s specified upper limit. Airflow velocities for HEPA filters in Grades B and C shall not exceed the manufacturer’s specified upper limit; and

* Pressure drop across filter must be within manufacturer’s specified limit.

HEPA Filters Designed for and Used at High Temperatures (e.g., >180o C) shall be verified under room temperature conditions at least twice per year

(every 5 to 7 months) by monitoring total airborne particulate levels in air that has passed through the HEPA filters, and shall not be subjected to particle challenge testing.

Integrity of Inaccessible HEPA Filters shall be established by an overall leakage test in which a particle challenge is introduced into the upstream side of the HEPA filter to establish an upstream aerosol concentration. A single downstream reading is obtained under turbulent flow in the duct. If any reading is greater than or equal to 0.01 percent of the upstream concentration, the filter shall be repaired or replaced.

A Confirmatory Retest of the HEPA filter integrity shall be performed after any repair.

HEPA Filter Repairs must meet the following criteria:

 *        Repairs must be made with materials acceptable to the Site principals responsible for the application where the filters are used;

*       Factory repairs shall not block or restrict more than 1 percent of the filter face area, and no single repair shall exceed 13 cm2 (2 in2);

*      No single field repair shall have a lesser dimension exceeding 3.8cm (1.5 in); and

*        Total repairs (factory and field) shall not exceed 4 percent of the filter face area.

Criteria for HEPA Filter Replacement shall include:

  *         Airflow or integrity test performance criteria are not met; or

*         The pressure drop across the filter exceeds the specified limit.

Temperature and Humidity Alert and Action Levels shall be based on:

*           Product moisture requirements;

*         Preclusion of condensate on room surfaces;

*         Minimized potential for static electricity; and

*         Operator comfort requirements.

Airflow Velocity in Grade A Environments shall be monitored when a HEPA filter is integrity tested and on a routine basis. Routine airflow velocities at a defined distance proximal to the work surface (e.g., 6 to 12 inches above the work surface) shall be monitored at designated representative locations.

Documented Challenges of Alarm Systems shall be performed at least once per year to ensure that the alarm systems are operational.

Total Airborne Particulate Shedding from High Temperature HEPA Filters in continuous belt dry heat tunnels with laminar airflow shall be minimized by methods that include, and are not limited to:

*         Ramp temperatures up and down relatively slowly; or

*        Bring an airstream to constant temperature and circulate it through the filters for a specified time period to remove particulates before the airstream is used.

Monitoring of Total Airborne Particulates and Airflow Velocity shall be documented at the time that the monitoring is performed. Documentation shall include and is not limited to:

* Date and time of monitoring;

* Identification of person performing the monitoring;

* Monitoring location;

* Monitoring instrument identification;

* Product and Batch Number or Lot Number identification;

* Results;

* Notation of any unusual occurrences (e.g., instrument sensor bumped during reading); and

*Rationale for invalidating any data and repeating the monitoring. All data must be retained.

Table 1: Air Handling Systems Performance Criteria

95 Percent ASHRAE Filters may be used instead of HEPA filters in a Grade D environment if sufficient pre-filtration and air recirculation are provided to enable consistently meeting Grade D requirements.

Smoke Mapping Studies are not required with continuous belt dry heat tunnels with laminar airflow.

K. Clean Steam Systems

This practice document defines the requirements for Clean Steam used in aseptic applications, and applications where the steam or condensate directly contacts products or materials, or direct product contact surfaces (i.e., equipment, Containers, Closures).

This document applies to GMP Production Sites and operations where clean steam is used in production activities for Pharmaceutical or Animal Health Drug Products, Active Pharmaceutical Ingredients (API), and Medical Devices .

Clean Steam shall be produced from one of the following types of water:

* Deionized Water (DI),

* Highly Purified Water (HPW),

* Purified Water (PW), or

* Water for Injection (WFI).

If DI or PW is used, Validation studies shall be performed to demonstrate that Bacterial Endotoxin will not be carried over in the steam.

If the clean steam generated is used solely in the production of ophthalmics or products with no bacterial endotoxin limits, the carry over studies are not required.

Clean Steam Generation and Distribution Systems used in the manufacture of API, drug products, and medical devices shall be designed to operate continuously, except when shut down for maintenance, and deliver clean steam at the specified pressure, temperature, and flow rate. Design of Clean Steam Systems shall include, and not be limited to:

 Validated feed water supply;

Polished or electropolished 304, 316, or 316L stainless steel sanitary piping, fittings, valves, instrumentation, and steam traps;

* In-line, continuous monitoring instruments and elements (I/E) to monitor system performance; Alarms to indicate if feed water or clean steam condensate quality does not meet specified requirements;

* Steam traps at the generator and all low points;

* Downward sloping pipes to drain points for complete drainage;

* Insulated steam pipes;

* Sample ports designed to prevent the formation/retention of condensate following sampling; and

* Sample ports at locations that will provide samples representative of the steam produced and the steam used.

Passivation of stainless steel clean steam generation and distribution systems, and the subsequent cleaning and testing, shall be performed before initial system startup of a New System, after major repairs, or if inspection of the system indicates the need to passivate to minimize corrosion of metal surfaces and to maintain steam quality.

Materials with Direct or Potential Contact with the Contents of the Clean Steam Distribution Systems, such as passivation chemicals, shall be Approved by the Site Quality Team. Testing and release requirements shall be defined by Specifications.

The Equipment shall be Commissioned and/or Qualified and the process for preparing clean steam shall be validated.

Clean Steam System Maintenance Measures shall include, at least, the following:

 Maintain feedwater system in a state of control;

* Monitor feedwater as Starting Materialfor clean steam;

* Monitor and maintain, within specified ranges, clean steam pressure, temperature, and Conductivity; and

* Preventive Maintenance (PM) for heat exchangers to assure integrity.

A Documented and Approved Monitoring Program for clean steam shall be established and include, at least, the following:

* Frequency of sampling and testing;

* Minimum specifications for chemical and bacterial endotoxin quality of clean steam condensate meeting stated specifications for WFI;

* Documentation and review of monitoring results, that include Trending;

* Bacterial endotoxin Alert Level and Action Level limits; and

* Documented Investigationsincluding corrective actions, when acceptable limits are exceeded.

Steam Quality shall be tested at a frequency based on historical data, risk analysis, and local regulatory requirements.

Clean Steam Condensate shall not be recovered for reuse in clean steam generation.

Clean Steam Generators shall be designed to include, and not be limited to:

* CalibratedI/E to monitor and record conductivity, temperature, and pressure;

* Alarm and automatic shut off devices;

* Properly designed double tube sheet heat exchangers to prevent Cross Contaminationfrom the plant steam to clean steam or its feedwater; and

*Steam trap to vent condensate and non-condensible gases at the generator.

Steam Traps shall be designed to:

* Discharge condensate without leaking steam;

* Discharge air and noncondensible gases from the system; and

* Be resistant to blockage.

Condensate Collection Systems shall be designed with atmospheric breaks to prevent back flow and contamination of the clean steam.

Point of Use Sampling Devices for Clean Steam shall be designed to prevent cross contamination with the cooling water. Procedures shall be established for the use, maintenance, and cleaning of the sampling devices.

Clean Steam Condensate Samples shall be labeled to include, at least, the following:

* Date;

* Time;

* Type of sample (e.g., clean steam condensate);

* Sample location identification; and

* Initials of sampler.

L. Aseptic Area Environmental Control

An Aseptic Processing Area (APA)Environmental Control Program shall be developed and shall be Approved by the Site Quality Team and Site Production Team.

This document applies to GMP Production Sites and operations where an aseptic environmental control program is used in production activities for Pharmaceutical and Animal Health Drug Products, Active Pharmaceutical Ingredients (API), and Medical Devices .

Aseptic Processing Areas shall be designed to minimize the risk of particulate and microbiological contamination. Design measures shall include, and not be limited to, the following:

* Airlocksand interlocking doors;

* Positive Pressure Differentials between rooms of different Air Classifications;

* Temperature and humidity conditions designed to minimize support for the growth of microorganisms;

* Air handling systems designed to minimize particulate and microbial contamination of materials being processed;

* Continuous, smooth, and non-porous floors, walls, doors, and ceilings free from ledges;

* Surfaces resistant to chipping, flaking, water, cleaning, and damage from Disinfectant agents;

* Coved corners, readily accessible for cleaning;

* Floor drains are prohibited;

* Equipment designed to be serviced as much as possible outside the APA;

* Unidirectional flow of equipment, Raw Materials, and product components maximized (e.g., material control and transfers performed by operators shall be designed to prevent introduction of contaminants from lesser into higher controlled areas); and Entry restricted to Qualified, gowned personnel.

Cleaning and Disinfection Procedures shall be designed to prevent contamination of equipment, Containers, Closures, drug products, APIs, and aseptically processed medical devices.

The Cleaning and Disinfection Program shall be documented and include, at least, the following:

* Provisions for evaluating cleaning and disinfectant products and their effectiveness in removing area specific soil and reducing Bioburden; and

* Provisions for use of disinfectant and Sporicidal Agents.

Cleaning and Disinfection Methods shall be Validatedand maintained under a documented change control program. Validation shall include, and is not limited to:

* Qualification of disinfectants and sporicidal agents to demonstrate that the agents are effective; and

* Demonstration that approved methods of application of disinfectants and sporicidal agents are effective.

Disinfectants shall be selected that are known to be effective against Disinfectant Indicator Organisms and/or environmental organisms routinely isolated from the facility.

Cleaning and Disinfectant Agents shall be purchased from an Approved Supplier and received in the same manner as raw materials. Testing and release requirements for these materials shall be defined by Specifications.

Qualified Personnel shall perform cleaning and disinfection of rooms and equipment following written and approved Standard Operating Procedures (SOP) and document the activities at the time the room or equipment is cleaned.

Cleaning Equipment (e.g., mops, wipes) shall be maintained in a sanitary condition: clean, dry, and stored off the floor. Cleaning equipment shall not be stored within the APA when not in use.

Containers or Items Likely to Generate Particles or Harbor Microorganisms (i.e., wooden items, corrugation) shall not be taken into APA or Preparation for Aseptic Areas (PAA). Paperwork shall be printed on specific materials designed and manufactured for use in controlled areas (e.g., autoclavable paper).

Cleaning and Disinfection shall be regularly scheduled and frequent. Daily and periodic cleaning and disinfection requirements shall be defined in written and approved SOPs. Sporicidal agents shall be used according to a written schedule and when environmental data suggest the presence of spore forming organisms.

APA Rooms and Equipment shall be cleaned and disinfected according to a defined schedule that includes cleaning and disinfecting after each use and at validated time intervals when not In Operation. Airlocks and gowning rooms shall be cleaned and disinfected, at least, daily when in use.

Rubbish and Used Garment Bins shall be emptied on a daily basis or more frequently to avoid excess accumulation. Receptacles for discarded over wraps shall not be located within critical processing areas (e.g., Grade A), while the area is in operation.

Floor Wax shall not be used in the APA.

Vacuum Cleaners Used in the APA shall be dedicated to the area and have HEPA Filters on the exhaust. HEPA filter replacement frequency shall be justified and specified in written, approved procedures. HEPA filters installed in APA vacuum cleaners shall be Integrity Tested at installation and at least every 5-7 months thereafter. Vacuum cleaners shall not be used during aseptic processing.

Only Materials, Equipment, or Tools that have been disinfected or Sterilized by a Validated Process shall be allowed in the APA.

Sterilized Materials, Equipment, or Tools shall be used within a validated time period or else they shall be removed from the APA and resterilized or discarded.

Equipment (e.g., mop heads, Sterilewipes) used to clean and disinfect in air classes Grades A to D shall be used in a manner designed to prevent Cross Contamination. Cleaning materials do not have to be sterilized for use in either Grade C or D areas. The need to sterilize cleaning equipment in a Grade C area depends on the intended use of the area. Methods for preventing contamination include, and are not limited to:

* Mops shall have non-porous inorganic handles (e.g., stainless steel, plastic);

* The mop head must be low particulate shedding (polyester, nylon or PVC), and compatible with the cleaning, disinfection, or sterilization process;

* Mop heads, mop handles, and buckets shall be resistant to rust or corrosion caused by exposure to cleaning and/or disinfecting agents (e.g., hypochlorite);

* Mop heads shall be discarded or cleaned and sterilized after each use. If mop heads are re-used, there must be an SOP that limits the number of times a specific mop head may be resterilized and re-used before it must be discarded;

* Buckets shall be made of non-porous inorganic material (e.g., stainless steel, plastic) and shall be cleaned after each use and sterilized prior to use; and

* Cleaning equipment shall be dry and stored in dedicated, well-ventilated storage cabinets or areas outside the APA.

Sticky Mat Sheets Used at Entrances or Exits to the APA shall be replaced at least daily or more frequently if they become visibly soiled. Re-usable mats must be washed at least daily, and more frequent if they become visibly soiled.

Cleaning and Disinfection SOPs shall describe, but not be limited to, the following:

* Cleaning schedules;

* Disinfectant concentration and method of preparation for use;

* Required cleaning equipment (e.g., mops, buckets, wipes);

* Detailed cleaning methods including sequential order in which the rooms are to be cleaned;

* The sequence for disinfection of production equipment;

* Allowable surface area to be cleaned before changing the cleaning solution;

* Cleaning requirements following such occurrences as, and not limited to, area maintenance, power outages, shutdowns, and loss or reduction in room air pressure differentials; and Cleaning and disinfection records.

Cleaning and Disinfectant Agent Selection Criteria shall include, and not be limited to, the following:

Type and number of microorganisms to be controlled;

* Type of contaminants to be removed;

* Type of surfaces (e.g., texture, porosity, materials of construction) to be cleaned;

* Method of cleaning and disinfecting (e.g., wiping, fogging, spraying);

* Compatibility with other cleaning and disinfection agents that are used concurrently;

* Non-reactive with surfaces to be cleaned;

* Toxicity and need for personnel to use safety equipment;

* Special storage, handling, Expiration Dating, or disposal requirements;

* Effect of residual disinfectant agent; and Potential for product contamination.

The Efficacy of Disinfectant Agents shall be qualified in the laboratory and under actual use conditions as follows:

* Laboratory tests to determine exposure time at expiration date shall be conducted with each disinfectant using the disinfectant concentration at which the disinfectant will be used in the APA against resident microbial flora;

* Disinfectants with sporicidal activity shall be challenged against bacterial and fungal spores;

* Medium Level Disinfectants shall be challenged against bioburden consisting of vegetative bacteria, yeasts, and fungal spores;

* Determination of the effect of materials of construction on resistance and performance of laboratory validation tests to validate application methods (e.g., spraying) shall be conducted using carriers made from the materials that constitute the most prevalent surfaces to be sanitized and any surfaces that could be difficult to sanitize using the most resistant organism found in resident bioburden flora;

* Upon completion of successful laboratory testing, the disinfectant shall be validated under in-use conditions in the manufacturing environment;

The Efficacy of Disinfectant Agents – continued from prior page):

* Evaluation of the disinfectant agent under in-use conditions shall include sampling from pre-determined high and low risk areas;

* Prior to in-use validation studies, the initial bioburden load of the equipment or facility surfaces must be determined;

* Equipment or facility shall be cleaned and disinfected according to written procedures; and

* Actual use conditions shall be monitored on ongoing basis as part of the environmental monitoring program.

Disinfectant Agents shall be purchased sterile or rendered sterile prior to use in the APA. Concentrated disinfectants do not have to be purchased sterile, but must be sterile at their use dilutions when used in Grade A or B areas.

Bulk Cleaning and Disinfectant Agents shall be diluted, stored, and used according to the manufacturer’s recommendations, laboratory validation results, and room or area requirements.

Containers for Cleaning and Disinfectant Agents shall be sterilized prior to filling if the containers are to be used in Grades A or B areas. Cleaning and disinfectant agents shall be used prior to the validated expiration date for the Subdivided material. Containers shall not be refilled (i.e., topped off) without resterilization of the containers.

Containers for Subdivided Cleaning and Disinfectant Agents shall be identified and include the following:

* Cleaning and disinfectant agent product name, site assigned Batch/Lot Number and dilution;

* Date prepared or sterilized and preparer initials, if applicable; and

* Validated expiration date.

Room Cleaning and/or Disinfection shall be documented and include, at least, the following:

* Areas and/or surfaces disinfected;

* Reference to the SOP used;

* Prior material or drug product including lot/batch number;

* Date and time of cleaning;

* Cleaning agent;

* Identification of the person who cleaned the room; and

* Identification of the person who Verified room cleaning.

Bottles of Sterile Disinfectant (e.g., Sterile 70 Percent Isopropanol) Used in the APA shall remain in the space of intended use until replaced. Bottles shall be replaced when empty or the specified shelf life has expired.