A. Inspecting for Manufacturing and Packaging Defects-Aseptic

B. Instructions for Manufacture of APIs and Drug Products

C. Uniform Practices for Manufacturing Operations

D. Personnel Qualification Program for Aseptic Processing Areas and Preparation for Aseptic Areas

E. Aseptic Processing Facility Environmental Monitoring

F. Use and Recovery of Solvents in API Manufacturing

G. Metal Detection

H. Weighing and Measuring Practices in Manufacturing Operations

I. Gamma Radiation Sterilization

J. Preventing Cross Contamination

K. Control of Manufacturing and Packaging Defects Non-Sterile

L. Sterilization/Depyrogenation Validation: Non-Product

M. Gowning Practices for Aseptic Processing Areas and Preparation for Aseptic Areas

N. Cleaning Depyrogenation and Sterilization of Containers and Closures

O. Sterilizing Filters and Filtration Systems

P. Moist Heat Terminal Sterilization of Aqueous Parenteral Products

Q. Media Fills for Sterile Drug Products and Aseptically Processed Medical Devices

R. Batch and Lot Identification

S. Aseptic Manufacturing Practices

A. Inspecting for Manufacturing and Packaging Defects-Aseptic

Sterile Drug Products and Sterile Medical Devices shall undergo inspection for manufacturing and packaging defects, after the drug product or medical device Containers are sealed. Qualified personnel authorized by the Site Quality Team shall perform the inspections as follows:

For Human Injectable or Implantable Products:

* A 100 percent inspection, on-line or off-line, of each sterile unit; and

* A second inspection, based on an Approved statistical sampling plan. For Human Ophthalmic Products, Topical Ointments, and Animal Health Products:

* An on-line or off-line inspection based on an approved statistical sampling plan.

This practice applies to GMP Production Sites performing aseptic manufacturing and packaging of sterile drug products, biologics, and sterile medical devices for Pharmaceutical, Animal Health.

Manufacturing and Packaging Defect Categories shall be established and include:

* Critical Defects,

* Major Defects, and

* Minor Defects.

Drug Products and Medical Devices shall be inspected for manufacturing and packaging defects using one or both of the following methods:

* Visual inspection, and/or

* Automated electronic system inspection. An Acceptable Quality Level (AQL) shall be established based on historical performance for each drug product and medical device at each plant Site for the following:

* Each defect category (i.e., critical, major, and minor); and

* Total number of defects found in the Batch/Lot.

Manufacturing and Packaging Defects shall be documented and Trended for each drug product, medical device, and container/Closure configuration. Automated Electronic Inspection Systems shall be Commissioned and/or Qualified.

Inspection Procedures must be written and approved and must include, at least, the following information:

* Inspection techniques for each type of drug product, medical device, and   container/closure configuration;

* Unique characteristics of the drug product or medical device; and

* Physical attributes that are considered defects.

Product Units shall be inspected for defects including, and not limited to, the following:

Drug Product in Glass or Plastic Containers

* Cracked or chipped containers;

* Low or high fill volume;

* Unusual appearance (e.g., off color, cloudy);

* Missing stopper and/or seal (cap);

* Leaking containers [i.e., fusion sealed and Form-Fill-Seal (FFS)] and

* Defective crimp and/or seal.

Lyophilized Drug Product

* Cracked or chipped containers;

* Missing stopper and/or seal (cap);

* Unusual appearance (e.g., off color);

* Unusual cake size (e.g., smaller/larger than normal);

* Evidence of Meltback;and

* Defective crimp and/or seal.

Drug Product in Tubes

* Defective crimps,

* Dented tubes, and

* Cap out of alignment.

Product Units shall be inspected for defects.

Medical Devices

* Cracked or chipped containers;

* Low or high fill volume;

* Unusual appearance (e.g., off color, cloudy);

* Missing stopper and/or seal (cap);

* Leaking containers [i.e., fusion sealed and FFS;

* Defective crimp and/or seal;

* Tear in packaging material; and

* Foreign Matter on packaging

Critical Process Parameters for Visual Inspections shall be established and shall include, and not be limited to, the following:

* Inspection rate, and

* Light intensity and position.

In addition, for automated delivery systems the following shall be considered:

* Conveyor/belt speed,

* Container inspection angle, and

* Container rotation speed.

Critical Process Parameter Ranges shall be established for each of the critical process parameters.

Inspection Personnel shall be qualified prior to inspecting drug products or medical devices and must pass a vision and color blindness test at least annually. In addition, whenever inspection personnel have not performed the inspection function for 3 months or more, they must be requalified. Qualification and requalification shall include, and not be limited to, the following:

* Identification and classification of defects for each drug product and container/closure configuration or medical device and container/closure configuration, using photos, illustrations, or actual defects as training aids;

*  Visual inspections;

*  Set-up and operation of automated delivery systems, if used; and

*  Set-up and operation of automated electronic inspection systems, if used.

Any Medical Condition that decreases visual acuity or color recognition shall be reported to the supervisor and the individual shall not perform inspections until medically cleared.

Visual Inspection Qualification shall include, and is not limited to, the following steps:

* Place a known quantity of defects that represent the typical Reject types in a defined number of product units;

* Set the conveyor delivery speed to the specified conveyor speed for the product and container/closure configuration;

* Visually inspect at the maximum (or fastest) inspection rate;

* Verify that the pre-defined number or percentage of defects was identified at the completion of the inspection; and

* Repeat the qualification a minimum of three times.

Visual Inspections shall include, and are not limited to, the following:

* Inspection rate not to exceed the maximum established rate for the product and container/closure configuration; and

* Scheduled eye breaks (e.g., 30-45 minutes).

*Critical Process Parameters for Automated Electronic

Inspection Systems shall be established and shall include, and not be limited to, the following:

*      Light position and intensity,

*      Conveyor/belt speed,

*      Inspection angle,

*    Container rotation speed, and

*      Reject mechanism (i.e., sensitivity setting).

Critical process parameter ranges shall be established during qualification for each of the critical process parameters.

Commissioning and/or Qualification of Automated Electronic Inspection System Equipment shall be performed and documented as described in and shall include, and not be limited to, the following:

* Calibration of Instruments and Elements (I/E);

* Verification that the equipment is installed according to the manufacturer’s Specifications;

* Determination of the reject mechanism setting for each product and container/closure configuration;

* Establishment of critical process parameter Operating Ranges; and

* Verification of proper machine operation and that specific defects (e.g., fill volume, particulates) are identified and rejected based on the sensitivity setting.

Performance Qualification (PQ) for Automated Electronic Inspection Systems shall include, and is not limited to, the following test:

* Set the equipment to operate within the established critical process parameter ranges for the product and container/closure configuration to be inspected;

* Place a known quantity of defects that represent the typical reject types in a defined number of product units;

* Verify that the pre-defined number or percentage of defects was identified at the completion of the inspection;

*  Inspect the same product units using visual inspection procedures;

* Verify that the automated inspection results are at least as accurate as the visual inspection results;

* Verify that the number or percentage of acceptable product units that are rejected by the automated electronic inspection system does not exceed a pre-determined acceptance limit (e.g., < 1.5%); and

* Repeat the qualification a minimum of three times.

Set-Up Procedures for Automated Electronic System Inspection Equipment shall include the inspection of a medical device or drug product test set, having a known

quantity of defects, prior to inspecting every batch/lot of medical device or drug product. Inspection of the test set shall result in the rejection of the known defective units.

Visual Inspection Station Design shall include, and not be limited to, the following:

* Light source (e.g., fluorescent, tindell beam, polarized) with an intensity of 100 to 350 foot-candles;

* Light positioned above, below, or behind the units to be inspected;

* Glare minimized;

* Matte black and matte white inspection backgrounds;

* Comfortable environment;

*  Easy access to product units; and

*  Designated areas for rejected and acceptable units.

Visual Inspection Station Maintenance shall include, and not be limited to, the following:

* Inspection background cleaned according to an approved schedule;

* Light source intensity periodically monitored and the light source replaced as needed;

* Inspection area clearly identified during inspections with product    identification and Batch or Lot Number; and

* Inspection area cleared of all unrelated product units, using line clearance   procedures, after the completion of the inspection.

Defective Units shall be rejected and separated from acceptable units. Rejected units shall be classified as to the defect category (i.e., critical, major, or minor) and the type of defect (e.g., missing stopper, low fill volume, cracked vial), and documented in the batch Record or Device History Record (DHR).

Defects shall be trended for each medical device, drug product, and container/closure configuration. An Investigation shall be conducted and documented when the number or percent of defects exceeds the AQL or when trends indicate a statistically significant increase in either of the following:

*      Number of specific defects, or

*      Total number of defects.

Procedures shall define batch/lot reinspection practices including, and not limited to, the following:

*      Conditions under which a batch/lot may be reinspected;

*      How many times a batch/lot may be reinspected;

*      Who shall perform the reinspection; and

*      Acceptance criteria for reinspected batches/lots.

B. Instructions for Manufacture of APIs and Drug Products

This practice document describes the preparation, Approval, and maintenance of manufacturing instructions for Active Pharmaceutical Ingredients (API), Drug Products, and registered over-the-counter (OTC) products manufactured by or for a GMP site for which site has the regulatory Chemistry, Manufacturing, and Controls (CMC) responsibility.

Instructions for the direct packaging of APIs from final processing and isolation, into bulk Containers for use or sale without further packaging, shall be included with the API Manufacturing Instructions.

If an API is repackaged into other containers and/or relabeled, such as for commercial sale or other internal uses, those activities are not within the scope of this document.

Master Manufacturing Instructions for APIs shall be based on the Regulatory Process Description (RPD) filed with the local Regulatory Authorities for the product market(s).

Master Manufacturing Instructions for Drug Products shall be based on the Composition and Manufacturing Description (CMD) filed with the local Regulatory Authorities for the product market(s) and shall be written to provide not less than one hundred (100) percent of Label claim.

Master Manufacturing Instructions shall be prepared by Qualified personnel and approved by the Site Production Team and Site Quality Team.

Manufacturing Batch Records shall be prepared for each Batch or Lot and shall be Verified by a qualified person to be an accurate reproduction of the Master Manufacturing Instructions. The person preparing the manufacturing batch records shall sign and date the record to indicate that it is the correct version, is legible, and all required pages are present.

For Validated Computerized Systems that make reproductions of the Master Manufacturing Instructions, this verification by a qualified person is not necessary, as it is covered by validation of the system. The verification shall be replaced by a check on the legibility of the printout.

Master Manufacturing Instructions must be complete and accurate, and describe in a logical order the sequence of activities necessary to manufacture the product.

Master Manufacturing Instructions and Batch Records shall be maintained under change control according to the Site Standard Operating Procedures (SOP).

Master Manufacturing Instructions shall be maintained under document management to ensure that only one currently approved master exists for each product process at a time.

Deviations from Manufacturing Instructions shall be Investigated and documented.

Master Manufacturing Instructions and Manufacturing Batch Records shall be retained according to Site record retention procedures.

Computerized Systems used to Prepare Master Manufacturing Instructions and/or Batch Records using Electronic Signatures and/or Electronic Records (e.g., electronic batch record systems) must be validated.

Each Master Manufacturing Instruction shall be uniquely identified with a code or numbering system to distinguish differences in strengths (drug products) or other unique product characteristics.

Master Manufacturing Instructions for APIs shall include, and are not limited to, the following information:

* API name and identification code;

* Batch size;

* A complete list of Raw Materials (RM) and Intermediates designated by names or codes sufficiently specific to identify any special quality characteristics (e.g., grade);

* An accurate statement of the quantity or ratio of each raw material or intermediate to be used, including the unit of measure;

* Production location and principal manufacturing equipment;

* Statement of expected yield, including the maximum and minimum range around the Theoretical Yield outside of which an investigation must be conducted;

* Processing instructions, including sequences to be followed, Critical Process Parameter Ranges, sampling instructions, In-Process Controls (IPC) and   acceptance criteria, and time limits for completion of critical processing steps and/or the total process;

* Instruction or reference to instructions for the storage of product including the container, Labeling, and any special storage conditions; and

* Any special precautions (e.g., protective equipment, gowning requirements).

Master Manufacturing Instructions for Drug Products shall include, and are not limited to, the following information:

* Product name, strength, and identification code;

* Batch or lot size;

* Description of dosage form;

* Name and weight or volume of each API per dosage unit or per unit weight or volume of product;

* Total weight or volume of dosage unit;

* A complete list of components, designated by names, and/or codes sufficiently specific to indicate any special quality characteristics (e.g., grade);

Accurate statement of the weight or volume of each component;

A statement concerning any calculated excess of a component;

* Statement of theoretical weight or measure and Accountability for components and product at critical phases of processing;

* Statement of expected yield including the maximum and minimum percentages of theoretical yield beyond which an investigation must be conducted;

* Instructions or reference to instructions to be used for preparing the critical equipment (e.g., cleaning, assembling, sterilizing);

* Processing instructions, including detailed stepwise instructions, critical process parameter ranges, sampling instructions, in-process controls and acceptance criteria, and time limits for completion of critical processing steps and/or the total process;

* Description of storage requirements for product including the container, labeling, and any special storage conditions; and

* Any special precautions (e.g., protective equipment, gowning requirements).

Manufacturing Batch Records shall be created from the Master Manufacturing Instructions and shall be used to record activities associated with manufacturing the batch.

Manufacturing Batch Records for APIs shall be used to document the completion of each significant step during the manufacturing of the batch or lot, and shall includ and are not limited to:

* Unique batch identification;

* Dates and times (if required) for each significant step

* Identity of Major Equipment (e.g., reactors, driers, mills) used;

* Weights, measures, and Batch Number or Lot

Numbers of raw materials, intermediates, or any Reprocessed materials used during manufacturing;

* Actual results recorded for Critical Process Parameters;

* Any sampling performed;

* Signatures or initials of the persons performing and directly supervising or checking each critical step in the operation;

* In-process test results;

* Actual Yield at key process phases or times;

* Description of packaging and label for intermediate or API;

* Representative label of API or intermediate if made commercially available; and

* Any deviation noted, its evaluation, and investigations conducted.

Manufacturing Batch Records for Drug Products shall be used to document the completion of each significant step during the manufacturing of the batch or lot, and shall include and are not limited to:

* Identification of the product and batch or lot;

* Dates and times (if required) of significant intermediate stages and of completion of production;

* Identity of individual major equipment used;

* Specific identification of each batch of components or In-Process Material used;

* Weights and measures of components used in the course of processing;

* In-process test results;

* A statement of the actual yield, accountability, and a statement of the percentage of theoretical yield at key phases of processing;

* Identification of the persons performing and directly supervising or checking each significant step in the operation; and

* Any deviation noted, its evaluation, and investigations conducted.

A Unique Batch Number or Lot Number must be assigned to each batch and appear on each page of the batch record.

C. Uniform Practices for Manufacturing Operations

This practice document defines dress code requirements for personnel whose job functions require potential contact with exposed Drug Products, Medical Devices, or Final Active Pharmaceutical Ingredients (API). These requirements shall be applied in conjunction with other process-specific dress code requirements [e.g., Aseptic Processing Area (APA) gowning procedures, personal protective equipment (PPE) procedures].

Personnel Performing Job Functions that Require Potential Contact with exposed product shall wear protective clothing that is designed to reduce the risk of product or personnel contamination.

This includes, but is not limited to, personnel from the following functional areas: Production, Quality, Packaging, Warehouse, Maintenance, and Laboratories (e.g., lab personnel that perform sampling in the production environment).

The Necessary Protective Clothing shall be worn by personnel as applicable to their operations. Particular attention shall be paid to the wearing of items of clothing, which are safety-related (i.e., PPE) and those, which are GMP-related (e.g., head covering, beard/moustache covering, gloves) as defined in Site Standard Operating Procedures (SOP).

A Clean Uniform or Protective Clothing, and Area-Dedicated Shoes or Shoe Covers shall be worn in production and production support areas where product is exposed (e.g., sampling booths, dispensary). Area-dedicated shoes and uniforms must be changed on a regular frequency defined in Site SOPs or sooner, if they become damaged or visibly soiled.

If used, shoe covers, must be removed when exiting the production area and new shoe covers must be worn upon return.

Visiting Personnel shall not enter areas of potentially exposed product unless there is an SOP in place to ensure that personnel and product will not be adversely affected by their entry. Visitors shall follow the same uniform/apparel procedures as company personnel.

Alternatively, visitors may be allowed to wear their street clothes instead of company uniforms provided that Site SOPs allow such a practice and temporary company uniforms or other protective clothing is worn over the street clothes in a manner that reduces the risk of product or personnel contamination.

Visiting personnel shall be escorted by a qualified colleague at all times while in the restricted area.

Changing Areas shall be designed to reduce the risk of product or personnel contamination [i.e., changing areas that have designated “clean” and “dirty” sides which are separated from each other by a barrier (e.g., door, air shower, bench) or are otherwise spatially separated (e.g., area designated by floor markings)].

Pictorial Examples shall be provided to show the correct dress practices.

Used Uniforms and Used Disposable Items shall be deposited in separate designated Containers outside the production area. These items must be removed from the area on a regular basis, as defined in Site SOPs.

In the Event of a Facility Evacuation (e.g., Fire Drill) personnel shall change into clean uniforms or coveralls prior to reentering the production area. When area-dedicated shoes are worn outside of the building, upon returning they shall be worn with shoe covers unless they can be cleaned or replaced with another pair of area-dedicated shoes.

Personnel Who Perform Job Functions That Involve Potential Contact With Exposed Product shall:

* Practice good hygiene;

* Not wear jewelry;

* Not wear makeup;

* Not wear false eyelashes;

* Cover hair, including facial hair, completely with hair covers;

* Not wear nail polish and not wear artificial nails; and

* Wear required protective garments (e.g., gloves, arm coverings).

Note: Medically necessary tags, such as medic alert tags, may be worn, but must be covered (under a glove or shirt) to ensure colleague safety and to prevent possible product contamination.

Items such as Contact Lenses maybe worn onlyif they are necessary to perform work duties. Care and protection (e.g., use of goggles) of such items shall be taken when working in direct contact with product.

When Putting on Clean Garments, personnel shall ensure that the garments are free from pins, clips, loose threads, and other Foreign Matter.

Protective Garments shall not be worn outdoors or in any cafeteria, bathroom, break room, or designated smoking area. Protective garments are those items of outer clothing worn in areas of potential product exposure in production, packaging, and warehouse areas (e.g., soft head coverings, beard and moustache covers, overshoes, coveralls, boiler suits, factory and laboratory coats).

Personnel Performing Job Functions that have Direct or Indirect Impact on Aseptic Processing shall follow the requirements of this practice.

D. Personnel Qualification Program for Aseptic Processing Areas and Preparation for Aseptic Areas

This practice document defines the Qualification requirements for Aseptic Processing Area (APA) Personnel, APA Support Personnel, Preparation for Aseptic Area (PAA) Personnel, and PAA Support Personnel. Records shall be maintained of all training.

This practice applies to Site GMP Production Sites performing aseptic operations for Sterile Active Pharmaceutical Ingredients (API), sterile Drug Products, Biologics, or sterile Medical Devices for Pharmaceutical or Animal Health.

Personnel Performing Job Functions That Have Direct or Indirect Impact on Aseptic Processing shall be qualified prior to being assigned to their job functions.

Re-Qualification Training shall be given to APA Personnel and APA Support Personnel, at least, once a year or when a colleague has not worked in the APA for a defined time period as determined by a documented Site risk-based analysis.

Knowledge Based Training for colleagues performing job functions in the APA or PAA shall include, but not be limited to, the following topics:

*      Overview of production process (including job functions and department roles and responsibilities);

*      Personal practices including hygiene;

*      Elementary microbiology; and

*      Principles of contamination control.

Skills Based Training for colleagues working in the APA or PAA shall be based on their specific job functions. Details of initial training and frequency of retraining shall be determined by the complexity of the task, skills necessary to complete the task, and the level of risk to meeting product Specifications if the task is not completed as per set criteria.

Required skills based training includes:

*      Training in specific gowning techniques for colleagues who work in the APA or PAA; and

*      Training in Aseptic Techniques and behaviour in the APA for colleagues who work in the APA.

Knowledge Based Training in Elementary Microbiology for colleagues working in the PAA or APA shall include, but not be limited to, the following topics:

*      Sources and spread of contamination; and

*      Site-specific microflora.

Knowledge Based Training in Principles of Contamination Control for APA and PAA Operators shall include, but not be limited to, the following topics:

*      Purpose of an environmental control program (Disinfection, Decontamination, and Sterilization of materials) including roles of cleaning, sanitizing, sterilization, and gowning in minimizing contamination;

*      Prevention of contamination of sterile equipment, Containers, Closures, In-Process Materials, Intermediates, APIs, drug products, and/or medical devices; and

*      Prevention of disruption of unidirectional airflow (UAF); and Airlock practices.

Effectiveness of Knowledge Based Training shall be measured using one of the four (4) levels of assessments described in this document.

Effectiveness of skills based training shall measure the competency of a colleague to perform a job skill through demonstration meeting predefined criteria [a level three (3) assessment].

These assessments shall be Approved by the Site Quality Team and Site Production Team

Skills Based Training on Aseptic Techniques and Practices for APA Personnel and APA Support Personnel shall include, but not be limited to, the following topics:

*      Effective Sanitization of gloves in the Critical Zone;

*      Practice of aseptic technique and applicable aseptic interventions (e.g., not blocking airflow, use of forceps, carrying materials in APA, aseptic set-up and connections, and proper movement and behaviour); and

*      Demonstration of airlock practices.

Skills Based Training in Gowning for APA Personnel or APA Support Personnel shall include, but is not limited to:

*      Demonstration by trainee of proper gowning techniques; and

*      Pass environmental monitoring of gloves and gown

Criteria for Initial Qualification of APA Personnel and APA Support Personnel shall include:

*      Knowledge based training;

*      Successful demonstration of gowning technique in accordance with Standard Operating Procedures (SOP);

*      Three (3) consecutive, acceptable gown and glove testing results conducted after gowning ; and

*      Skills based training on applicable job skills including demonstration of competence; and

*      Participation in a successful aseptic processing simulation including performance of predefined job skills.

Criteria for Annual Re-Qualification of APA Personnel and APA Support Personnel shall include:

* Knowledge based training (i.e., review of material focusing on areas of concern or interest for area/department, information to build on existing knowledge level of personnel);

* Successful demonstration of gowning technique in accordance with SOPs;

* Acceptable gown and glove testing results;

* Skills based training on applicable job skills including demonstration of competence, if identified in Risk Assessment; and

* Participation in a successful aseptic processing simulation including performance of predefined job skills.

Re-Qualification Training shall be given to APA Personnel and APA Support Personnel when an employee has not worked in the APA for a defined time period as determined by a documented Site risk-based analysis. Such re-qualification shall include:

*      Review of knowledge based training;

*      Successful demonstration of gowning technique in accordance with SOPs;

*      Acceptable gown and glove testing results;

*      Skills based training on applicable job skills including demonstration of competence; and

*      Participation in a successful aseptic processing simulation including performance of predefined job skills.

Visiting Personnel shall complete the following prior to being escorted in the APA:

*      Training in applicable Site SOPs including gowning practices; and

*      Successfully pass one gown and glove monitoring.

E. Aseptic Processing Facility Environmental Monitoring

An Environmental Monitoring Program shall be implemented at all Aseptic Processing Facilities. This practice document applies to aseptic processing facilities for Sterile Active Pharmaceutical Ingredients (API), Drug Products, Biologicals, and Medical Devices for Pharmaceutical and Animal Health.

Environmental Monitoring in Aseptic Processing Facilities Where Sterile APIs, Sterile Drug Products, and Sterile Medical Devices are manufactured shall include the following:

* Microbiological Active Monitoring expressed as total cfu (bacteria and fungi) and each reported separately;

* Total Airborne Particulates (microorganisms and Non-Viable);

* Microbiological Passive Monitoring;

* Microbiological testing of equipment and surfaces using Contact Plates, swabs, or Flexible Agar Plates; and

*Microbiological testing of personnel using Touch Plates and contact plates

Environmental Sampling, Testing, and Evaluation of Test Results shall be performed by Qualified personnel.

Air Sampling in Critical Zones shall be performed in a manner that minimizes contamination risk to the product.

Environmental Monitoring Sampling Frequencies for Grades A and B (Grade A Background) must be substantiated by a documented risk assessment.

Routine Microbiological Monitoring Methods Used in Aseptic Processing Facilities shall be designed to detect microorganisms that have the potential to contaminate the environment. Such methods shall be able to detect the following:

*      Bacteria,

*      Yeast, and

*     Mold.

Alert Levels and Action Levels shall be established for each Air Classification and shall be specific for the area being monitored. The levels shall be developed based on an analysis of historical data and shall not be greater than those cited in this practice or applicable regulatory requirements. Alert and action levels shall be evaluated on, at least, an annual basis and the alert and action levels revised to represent the current monitoring data.

The Environmental Monitoring Program shall define the response, corrective actions, and follow-up review required for alert and action level excursions.

The Site Quality Team and Site Production Team shall approve all Investigations and corrective actions when action levels are exceeded.

A System shall be in place for:

* Notification of responsible authorities within one Business Day when environmental monitoring data exceed action levels;

* Initiation and documentation of investigations and corrective actions;

* Completion of corrective actions; and

* Site Quality Team approval of the environmental data prior to release of any potentially affected Batch/Lot.

*Routine Environmental Data shall be reviewed and Trended on a periodic basic (e.g., monthly, quarterly, annually).

The Site Quality Team is responsible for review of all aspects of the environmental monitoring program including, but not limited to, the following:

*      Microbiological environmental sample testing and review of the test data;

*      Total airborne particulate monitoring and data review;

*      Review of routine environmental data trends;

*      Review of alert and action level summary analyses, at least, annually; and

*      Annual reviews of environmental results to determine if there is a need to modify the environmental monitoring program.

Non-Compendial Environmental Monitoring Test Methods (TM) shall be Validated for their intended use.

Equipment (e.g., Particle Counters, Centrifugal Samplers, Anemometers) Used to Collect Environmental Samples shall be Calibrated according to the equipment’s use and performance history and used within their established calibration frequency.

Microorganisms from Routine Environmental Monitoring Samples Including Personnel Monitoring shall be characterized using a Protocol designed to identify to the genus level (for bacteria and yeast, to the species level) those microorganisms isolated from Grade A and B (Grade A background) environments and when action levels are exceeded in all other air classifications. A periodic identification of microflora (to at least the genus level) from Grade B (not Grade A background), Grade C and D areas shall be performed.

Environmental Monitoring Data Review shall be performed as a part of the batch record review or Device History Record (DHR) review.

For In Operation Conditions, environmental monitoring shall be performed according to established frequencies and not less frequent than shown in Table 1.

Standard Operating Procedures (SOP) shall define when environmental monitoring is performed.

Areas to be Monitored shall include air classifications Grade A through Grade D.

Sampling Location Selection Criteria shall be documented and justified based on factors including, and not limited to:

* Location likely to be a source of product contamination;

* Locations likely to have a high potential for microbial presence;

* Locations likely to be difficult to clean and sanitize;

* Historical data;

* Qualification data;

* Production activities;

* Line configuration; and

* Personnel, product, and/or material traffic patterns.

The Environmental Monitoring Program shall include documentation of sampling locations including:

*      Area diagrams with sampling locations;

*      Type and frequency of sampling at each sampling location, including provisions for sample rotation;

*      Microbiological monitoring of all sites in Grade A through Grade D areas during in operation conditions. This includes set-up in Grade A areas; and

*      Provisions for sampling additional locations at the discretion of the sampler, including documentation of sampling location and reason for selecting the site.

Microbiological Environmental Sampling Results shall be reviewed by the Site Quality Team within one business day of data being recorded.

Microbiological Environmental Sampling and Personnel Monitoring shall be performed by qualified personnel authorized by the Site Quality Team. The practice of unobserved self-sampling is not allowed.

Total Airborne Particulate Monitoring shall be performed by qualified personnel authorized by the Site Quality Team. The Site Production Team and the Site Quality Team shall review the data.

Microbiological Environmental Monitoring, Personnel Monitoring, Temperature, Humidity, and Pressure Differential Data shall be tabulated and trended using tools such as spreadsheets, graphs, or charts, to show cumulative data and highlight all alert and action levels.

Microbiological Environmental Monitoring Trends shall be analyzed by the Site Quality Team for:

*      Increases and decreases in Microbial Populations over time;

*      Changes in the types of microorganisms identified;

*      Need for increased or decreased monitoring;

*      Establishment of alert and action levels (expected absence of microbial growth for Grade A areas);

*      Need to change alert and action levels [alert and action levels shall only be lowered (i.e., tightened) based on historical data]; and

*      Need to recertify or retrain individuals in personnel gowning practices.

Microorganisms isolated from the environment shall be characterized as follows:

*      Bacteria and yeast microorganisms shall be characterized to species level when isolated from Grade A or B (Grade A background) and from personnel glove and gown samples, and when action levels are exceeded in any areas. An identification scheme shall be designed to identify microorganisms to the species level. If the isolate cannot be identified using this scheme, scientific justification must be provided; and

*      Mold colonies shall be identified by colonial and microscopic morphology and documented (e.g., drawings, published references, photographs) when isolated from Grade A through Grade D areas.

Provisions for Increasing Environmental Sampling Frequency shall be determined by the Site Quality Team and shall be based on, and not limited to, the following:

*      Upward trends in environmental monitoring data,

*     nstallation of new equipment,

*     Modifications to existing equipment,

*      Increases to the number of personnel in the Aseptic Processing Area (APA) or increases to the number of operating shifts,

*      Changes in aseptic practices, and

*      Sterility test or Media Fill failures.

Environmental Monitoring Action Levels for Microorganisms and Total Airborne Particulates shall be established based on historical data but must not exceed the levels shown in Table 2.

Alert Levels shall be established for microorganisms and total airborne particulates based on historical data for each air classification, and shall be documented and trended.

Consecutive Alerts Levels at any given location and multiple alerts within one sampling period shall be equivalent to an action level.

Invalidation of Environmental Results due to a false positive or a testing artifact requires an investigation and written justification approved by the Site Quality and Production Authorities.

Passive Monitoring Using Settle Plates shall be performed continuously when in operation. The settle plates shall be positioned in areas of greatest risk of product contamination (e.g., sites of line intervention, near filling needles). Exposure conditions and time shall be validated and preclude dehydration of the media that can inhibit the recovery of microorganisms.

Active Monitoring for Microorganisms shall be performed using a calibrated volumetric sampling device (e.g., slit-to-agar, centrifugal sampler). Sample volume must be greater than or equal to one cubic meter for Grade A and Grade B areas. Sample volumes for Grade C and Grade D areas shall be sufficient to detect contamination at the level of Quantitation.

Monitoring for Total Airborne Particulates shall be performed using a calibrated particle counter.

Surface Monitoring for Microorganisms shall be performed using contact plates or flexible agar plates for flat surfaces and swabs for irregular, difficult to reach areas. Residual media shall be removed from the sampling location immediately (e.g., using a sterile alcohol wipe).

Gown Monitoring Using Sterile Contact Plates shall be conducted in the APA prior to entering the degowning room as follows:

*      APA Personnel and APA Support Personnel who function in the critical zone and in non-critical areas shall be monitored as indicated in Table 1;

*      Sample the inside or underside of each gown sleeve between the wrist and elbow;

*      Sample a zipper or chest position on the gown; and

*      Personnel shall exit after gown sampling.

Glove Monitoring Using Sterile Touch Plates or Contact Plates shall be conducted in the APA prior to entering the degowning room as follows:

 *     APA and APA Support Personnel who function in the critical zone and in non-critical areas shall be monitored once per shift (e.g., upon first exit from the APA);

*      No glove sanitization immediately before sampling;

*      Sample all fingers of both gloved hands; and

*      Clean gloves after sampling to remove residual media.

Personnel Monitoring in Grade A Areas shall be performed where special applications involving complex manual activities justify such measures (e.g., transfer of biological fluids in biosafety hoods).

Room Pressure Differential Levels shall be controlled, continuously monitored, and recorded.

Temperature and Humidity Levels shall be controlled, continuously monitored, and recorded for products, requiring such control.

Validation of Microbiological Environmental Monitoring Test Methods shall include, and not be limited to, the following:

* Media selection and exposure time;

Growth Promotion Testing (including at least one environmental isolate);

* Efficacy and stability of the neutralizing agents (e.g., penase);

* Incubation time and temperature; and

* Microorganism identification methods.

Purchased Ready-To-Use Microbiological Culture Media shall be:

* Suitable for the detection of microorganisms [e.g., Sabourand Dextrose Agar (SDA) or Tryptic Soy Agar (TSA)] and when necessary (i.e., if used in areas where product might inhibit growth) contain neutralizers to inactivate sanitizers and/or antimicrobial drug products;

* Used only after it has been approved for use upon successful growth promotion testing;

* Stored under conditions recommended by the Supplier for prepared media;

* Inspected for visible microbial contamination prior to use;

* Incubated as quickly as possible with the time between exposure and incubation not to exceed twelve (12) hours unless supported by data; and

* Used within its Expiration Date.

In-House Prepared Microbiological Culture Media shall be:

*      Suitable for the detection of microorganisms (e.g., SDA or TSA) and when necessary (i.e., if used in areas where product might inhibit growth) contain neutralizers to inactivate sanitizers and/or antimicrobial drug products;

*     Used only after it has been approved for use upon successful growth promotion testing;

*      Stored under validated conditions;

*      Inspected for visible microbial contamination prior to use;

*      Incubated as quickly as possible with the time between exposure and incubation not to exceed twelve (12) hours unless supported by data; and

*      Used within its laboratory qualified expiration date.

Separate Microbiological Growth Media shall be used for the detection of bacteria and a differential medium for the detection of fungi (e.g., SDA). Exposed media shall be incubated and monitored as follows:

*      Bacteria specific media at 30 -35o C for a minimum of five (5) calendar days;

*      Fungi specific media at 20 -25o C for a minimum of five (5) calendar days; and

*   Check for growth, at least, at the end of the incubation period.

Growth Promotion Testing shall be performed successfully on all lots of prepared media prior to being approved for use. Testing must demonstrate that the media can support the growth of a selected panel of microorganisms that includes, at least, one microorganism found in the environment.

An Environmental Monitoring Report, which might prompt an investigation and corrective actions, shall be completed when environmental conditions exceed specified alert or action level ranges. Such reports shall be included in all batch/lot records or DHRs potentially affected. The report shall include a complete sample description (e.g., location, type of sample, test results, affected lot/batch).

An Investigation shall be conducted whenever an action level is exceeded. The investigation shall include, and not be limited to:

*      Identification, if possible, to the species level of microorganism(s) associated with an action level;

*      Establish, if possible, a cause and effect relationship between the observed growth and possible source(s) of contamination;

*      Corrective action measures;

*     Identification of any additional lots or batches which may be impacted; and

*      A completed investigation approved by the Site Quality Team and Site Production Team within thirty (30) calendar days and prior to lot/batch release.

If the investigation will go beyond thirty (30) calendar days, an interim status report must be issued by the Lab Supervisor to the Site Quality Team.

Each Environmental Sample shall be labeled with a unique identification code that is traceable to the environmental sampling record.

Environmental Sampling Records shall include, and shall not be limited to, or reference the following information:

*      Date and time of each sample;

*      Identification of person obtaining the sample;

*      Identification number of sampling equipment, if applicable;

*      Sample location and area;

*      Culture media batch identification;

*      Incubator identification number;

*      Incubation temperature;

*      Date and time incubation initiated;

*      Date and time incubation terminated;

*      Product and Batch Number or Lot Number identification; and

*     Identification of each person sampled.

A Personnel Environmental Monitoring Log shall be established and reviewed daily by the Site Quality Team to verify all personnel working in the APA are monitored as indicated in Table 1 prior to leaving the APA.

Environmental Sampling Records and Results shall be included or referenced in the batch record or DHR.

Table 1: Aseptic Processing Facilities Environmental Monitoring Frequency

Table 2: Action Level for Microorganisms and Total Airborne Particulates

In the Case of Filling Sterile Powders or Aerosols it is acceptable that it may not always be possible to demonstrate conformity with total airborne particulate standards at the point of fill when filling is in progress, due to the generation of particulates or droplets from the product itself.

When Using One General Purpose Culture Medium (e.g., TSA) for the detection of both fungi and bacteria, the medium selected and incubation conditions must beshown (e.g., validated and documented) to give results equivalent to the use of two separate media for these organisms.

Incubate at 20 -25o C for seventy-two (72) hours followed by forty-eight (48) hours at 30 -35o C.

For Products Filed with the European Union (EU), the recommended limit for microbiological monitoring of Grade A areas during operation is

<1 cfu/m3 . These are average values.

For Products Marketed in the EU the results from personnel gown microbiological monitoring may be averaged. This does not include gloves.

For Products Marketed in the EU, airborne classification of production areas includes monitoring for particles ≥5µm.

F. Use and Recovery of Solvents in API Manufacturing

This practice document applies to the offloading, use, and recovery of Solvents used in the commercial manufacture of Active Pharmaceutical Ingredients (API)and Intermediates including the following:

*      Virgin solvents,

*     Recycled Solvents, and

*   Recovered Solvents.

The processing and use of solvents must be established, controlled, and monitored based on the potential impact on intermediate or final API product quality.

This document applies to GMP Production Sites where solvents are used in the manufacturing of APIs and/or intermediates.

Offloading, Processing, and Use of Solvents, including recycling and recovery, shall be established, controlled, and monitored according to Standard Operating Procedures (SOP).SOPs for offloading, processing, and/or use of solvents that directly affect the quality of the solvent and/or product must be Approved by the Site Quality Team and Production Team.

Solvent Recovery, Recycling, and Off-Loading Activities must be performed by Qualified personnel.

Solvents shall meet Specifications suitable for their intended use and any applicable Regulatory Specifications (RS).

Solvents shall be Reevaluated at predetermined intervals to assure continued suitability for use.

Use of Solvents in manufacturing shall be documented for purposes of traceability.

Controls shall be in place to ensure that solvents restricted to a particular use are not used in another process.

Changes to Processes and Specifications for Recovered and Recycled Solvents (including recycled distillates) shall be documented and approved in accordance with Site Change Control SOPs.

Recycled Solvents must be characterized for degradants and/or other impurities including impurities that are product-related or from other solvents. The characterization must span the timeline over which the recycled solvent will be stored and/or used. The characterization shall be documented and include relevant data and/or documented scientific justification for the reuse of the solvent.

If Solvent is Recovered or Recycled, reuse in the same or different process from which it originated is permitted provided the recovery or recycling process is controlled and monitored and the recovered or recycled solvent meets suitable specifications before use or commingling with other approved materials.

When Establishing Impurity Limits for Recovered Solvents Intended for General Site-Wide Use, the following must be considered:

*      Capability of the solvent recovery equipment and process;

*      The volatility of potential contaminants (e.g., other solvent impurities, reactants, intermediates, and side products); and

*      The potential for contaminants to be carried over in the recovered solvent.

For External Contract Vendors of Recovered Solvents to a Site, the responsible Site Quality Team shall assure that the methods, facilities, and controls (e.g., measures for storage, loading, shipping, and unloading of the recovered solvent) used by the contract vendor meet the requirements in this document including, and not limited to, the following:

* Site Audit Report available indicating acceptability;

* Contract approved by both parties;

* Quality Agreement;

* History of use, if the equipment is used to recover solvents from non-Site firms;

* Acceptable cleaning of equipment; and

* Solvents must meet Site specifications.

Virgin and Recovered Solvents can be combined if testing has shown that each is suitable for all manufacturing processes in which they are intended to be used. If approved recovered solvent is mixed with virgin solvent, the mixture shall be restricted to the approved uses of the recovered solvent.

Solvent Recovery and Recycle Processes must be described and documented in approved Instruction-Records, which include, and are not limited to:

 *     A description of the processing steps, including the order in which they are conducted;

*      Solvent characteristics;

*      Any testing (in-process and/or release) performed, including specifications;

*      Process Parameters;

*      Process parameter ranges;

*      Description of materials, including quality and quantity, used in the processing of the solvent (e.g., pretreatment materials, entrainers);

*      Equipment used for the recovery; and

*      Any recovery or recycle equipment preparations.

In-Process Controls (IPC), if performed, shall meet acceptance criteria that are designed to ensure the recovered solvents are suitable for their intended use.

Routine Analytical Tests must be used to demonstrate that each recovered solvent Lot meets its established release specifications. Such analytical tests must be Validated.

Direct Impact Solvent Distribution and Storage Systems shall meet Qualification requirements. Design of such systems shall include consideration of, and is not limited to, the following:

* Material(s) of construction; and

* Backflow control measures to prevent Cross Contamination.

Solvents from Processes Requiring Dedicated Facilities for a Product Family (e.g., penicillins and cephalosporins) shall not be recovered for reuse into product families different from the processes from which they originated.

Solvent Recovery Processes shall be Validated if the resultant solvent will be used in an intermediate or API process other than the process from which the solvent originated, including general Site-wide use. The validation shall be conducted according to an approved validation plan and the requirements.

For Solvent Recovery Processes Requiring Validation, the qualification status of direct impact systems and validation status of critical operations must be evaluated and documented. Direct impact systems and critical processes to be considered include, and are not limited to:

*      Analytical Methods;

*      Utilities;

*      Facilities;

*      Equipment;

*     Computerized Systems; and

*      Cleaning procedures.

Validation of the Solvent Recovery Process must include characterization of the incoming solvent stream including identification of the quality attributes for that stream and operational variations in the generation of the recovery feedstock over an extended period of time (e.g., three to six months).

For Solvent Recovery Deviations or Failures that directly affect the quality of the solvent and/or product, there shall be an Investigation and documentation.

Systems and/or Controls must be in place to prevent unauthorized off-loading of bulk solvents (e.g., Tanker Truck, Railcar).

A Certificate of Cleaning is required for all bulk solvent deliveries in non-dedicated bulk Containers. Additional assurances that there will be no cross contamination from the bulk container shall include consideration of, but are not limited to, the following:

*      Testing for trace impurities (e.g., non-specific volatile and/or non-volatile impurity testing); and

*      Audit of the supply chain (e.g., solvent Supplier, carrier).

A check of the cleaning certificate prior to offloading is required and a copy of the certificate must be retained in accordance with Site record retention SOPs. An investigation shall be conducted and documented when a bulk container arrives with no cleaning certificate. The investigation must be reviewed and approved by the Site Quality Team.

Shipping Documentation must accompany the bulk solvent delivery and shall be retained.

Location of Tamper Evident Seals on Bulk Solvent Containers shall be defined in a Site SOP and shall be checked prior to solvent offloading. These seals are only to be removed by, or in the presence of Site personnel. An investigation shall be conducted and documented when a bulk solvent container arrives with broken or absent seal(s). The investigation must be reviewed and approved by the Site Quality Team.

Prior to Bulk Solvent Container Off-Loading, when a Certificate of Analysis (COA) is not used for release of solvents, testing shall be conducted following approved Test Methods (TM), and the test results must meet approved specifications.

At a minimum, an identity test is required whether or not the solvent is released based on testing or a COA, unless sampling the solvent presents a hazard to personnel and/or facilities. Hose connections from the bulk solvent container to a storage tank shall not be made until the bulk solvent container contents have been approved. Authorization to off-load approved material must be explicit and documented (e.g., using either a validated electronic system or a paper system).

The Bulk Solvent Container Unloading Connection Point shall, at a minimum, be visually inspected for cleanliness and the inspection documented prior to the hose being connected. Product contact surfaces of multi-use hoses used in solvent offloading shall be cleaned, drained, labeled, and protected from the environment. Non-dedicated Site off-loading pumps shall be cleaned to the same standard as the hoses.

Bulk Solvent Container Samples, When Required, shall be taken by, or in the presence of, Site personnel using approved sampling methods. Sampling equipment must be made of non-reactive, non-additive, and non-absorptive material (e.g., 316L stainless steel). The sampling equipment must be clean and stored protected from the environment.

Traceability of Solvents from Bulk Solvent Off-Loading shall be maintained.

G. Metal Detection

This practice document applies to GMP Production Sites and operations responsible for metal detection in Pharmaceutical and Animal Health solid oral dosage form Drug Products. It also applies to Medical Devices that by design do not contain metal components.

A Program of Systems and Controls shall be developed at each Site to preclude potential metal contamination of products.

The Site Quality Team shall decide if routine metal detection operations are required at their Site. The decision made by the team and the supporting rationale shall be documented.

A Product Batch/Lot shall be passed through a metal detector only once during a specific manufacturing or packaging stage, when a metal detector is used to isolate and Reject material containing metal particles that are suspected or known to be present in the batch/lot.

Use of a Metal Detector for Recovery or Re-inspection must be authorized by the Site Quality Team. An Investigation report must be completed prior to approval to use the metal detector for recovery or re-inspection.

Metal Detectors shall not be used in an attempt to render a batch/lot acceptable when there is evidence that the metal contamination is diffused throughout (pervasive) every part of a lot (e.g., broken screen at blender charging station, metal parts scraping against each other during tabletting process, Supplier notification of metal in Raw Materials).

Metal Detectors shall be qualified prior to use. Qualification of metal detectors shall include Installation Qualification (IQ) and Operational Qualification (OQ).

An Action Level, not to exceed 0.01 percent of the total number of units isolated by a metal detector and confirmed as having metal, shall be established and Approved by the Site Quality Team, based on historical performance, for each drug product or medical device processing stage where metal detection is performed.

An Investigation shall be conducted and documented when the number of metal containing units isolated exceeds the action level, or when there is a process Deviation that is known to have possibly caused metal contamination. Location of Metal Detectors, when installed for routine metal detection, shall be approved by the quality team and shall include consideration of design, location, and arrangement of manufacturing and/or packaging process, and equipment.

Metal Detector Installation and Routine Set-Up shall be completed according to the equipment manufacturer’s Specifications. Environmental conditions to be considered

when setting up the metal detectors shall include, and are not limited to:

* Product noise history for setting sensitivity parameters;

*Electromagnetic interference;

* Vibrations;

* Electrostatic charging; and

* Electromagnetic interference with other equipment and other potential sources of electromagnetic waves.

All Equipment Settings During Operation must be within the acceptable ranges established during qualification or Validation trials for each product or group of products with the same product signal noise.

Preventive Maintenance (PM) shall be performed for each metal detector at least annually, following vendor recommendations. All technicians performing Calibration or maintenance activities must be Qualified.

All Product Contact Parts of metal detectors shall be cleaned after use, following a Validated cleaning process. Equipment shall be removed from the manufacturing or packaging line, when possible, for cleaning.

H. Weighing and Measuring Practices in Manufacturing Operations

This practice document applies to weighing and measuring of materials used in the manufacture of Drug Products, Active Pharmaceutical Ingredients (API), Medical Devices, and Intermediates.

This document applies to all GMP sites where intermediates, APIs, drug products, and medical devices are produced for Pharmaceutical or Animal Health.

System shall be established and maintained at the site to assure that materials (e.g., Starting Materials, Raw Materials (RM), and APIs) used in the manufacturing process

are weighed or measured under conditions that will not affect the fitness-for-use of the material in the manufacturing process.

For materials which do not require Subdividing, and are purchased from Approved Suppliers with weighing practices that have been audited and found acceptable to Site, the weight indicated on the Container label by the Supplier may be accepted in lieu of reweighing and transferring the materials to another container.

Methods for Weighing and Measuring Materials shall be established and maintained according to Standard Operating Procedures (SOP) and shall be Approved by the Site Quality Team and Production Team.

Methods for Weighing and Measuring shall be accurate and repeatable over the range of weights or measures for which the methods are used.

Weighing and Measuring Operations shall be performed by Qualified personnel.

Containers of Weighed or Measured Materials Being Dispensed for Manufacturing Use shall be labeled to clearly identify the contents and any special handling requirements.

The Identities and Actual Quantities of Materials being prepared for manufacturing use, unless determined by a Validated automated system, must be Verified by a second person (commonly known as a Dual Witness).

Actual Quantities of Materials Used in the Course of Processing shall be documented in the Manufacturing Batch Records for the API or drug product, or in the Device History Record (DHR) for the medical device.

Routine Calibration, Periodic Operational Checks, and Maintenance of scales and balances and cleaning of dispensing modules or areas shall be conducted and documented according to approved schedules and procedures.

Personnel Performing Weighing and Verifying Operations shall wear protective clothing to minimize contamination of the equipment and materials, when materials are exposed.

Accurate Inventory Records shall be maintained for each material used in manufacturing to enable reconciliation and tracking the use of the materials.

Materials shall be inspected and verified prior to weighing and measuring to assure they are the correct materials as specified in the manufacturing instructions for the product (e.g., correct grade). Verification of materials shall include, and not be limited to, the following:

 *     Identity;

*      Lot Number;

*      Status (i.e., Approved); and

*      Expiration Date or Reevaluation Date.

Each Weighed and Measured Material shall be dispensed into a clean, non-reactive container, and identified so that at least the following information can be determined

(e.g., barcode):

*      Material name and item code;

*      Lot number; and

*     Weight or measure of material in the container.

In addition, for drug products, this identification shall also indicate the Batchor Lot for which material was dispensed, including its product name, strength, and lot number.

Each Container of Material Dispensed to manufacturing shall be examined by a second person, unless a Validated Computerized System is used, to assure that:

*      The material was approved by the Quality Team;

*      The weight or measure is correct as stated in the batch manufacturing instructions; and

*      The containers are properly identified.

Recording of Weights and Measurements shall be completed at the time each action is performed. Any alterations shall be signed and dated with the original entry legible, and the reason for the alteration recorded.

I. Gamma Radiation Sterilization

This practice document establishes the requirements for Validation of gamma radiation Sterilization processes used to sterilize Active Pharmaceutical Ingredients (API), Drug Products, Medical Devices, and non-product items, such as, APA Gowning Articles, Containers, and Closures with direct or potential contact with Sterile Raw Materials (RM), APIs, drug products, or medical devices.

This practice applies to GMP Production Sites performing gamma radiation sterilization or using Contract Vendors for gamma radiation sterilization of Pharmaceutical or Animal Health products or materials.

Gamma Radiation Sterilization Processes shall be validated. Equipment used to perform gamma radiation sterilization shall be properly designed and Commissioned and/or Qualified according to.

Critical Process Parameters and Critical Process Parameter Ranges shall be identified during the validation process for each API, drug product, medical device, and non-product item sterilized by gamma radiation.

Contract Gamma Radiation Sterilizers shall be accepted only after an audit has been conducted that establishes the Contract Vendor’s validation studies, operations, and facilities are consistent with this practice.

Validation Studies for Gamma Sterilization shall be performed by Qualified personnel according to Approved Protocols and Final Validation Reports reviewed and approved by the Validation Committee (VC).

A Quality Agreement shall define the responsibilities of the contract gamma sterilization facility management and the Site Quality Team for, and not be limited to:

* Execution of the validation of gamma radiation process in conformance with site VC approved protocols;

* Sterilization of site products and non-product items according to validated processes;

* Investigation, documentation, and notification of Site Quality Team of Deviations occurring during the sterilization process;

* Review of sterilization documentation;

* Providing a copy of sterilization documentation to Site Quality Team;

* Notification of Site Quality Team of any intended change potentially affecting validation;

* Performance and review of Dose Audits; and

* Maintenance of sterilization equipment and Calibration of Instruments and Elements (I/E).

Suitability of Gamma Radiation Sterilization for each sterile drug product, API, medical device, or non-product item shall be documented. Gamma radiation compatibility studies shall be performed at a dose beyond the required radiation sterilization dose [e.g., twenty-five (25) -fifty (50) percent above the required dose] to demonstrate that the radiation dose does not have an adverse effect over the intended shelf life of the products or items. Such studies can be conducted on pilot or lab scale Batches.

Dose Setting to Determine the Minimum Absorbed Dose needed to sterilize APIs, drug products, medical device, or non-product items shall be based on one of the following Association for the Advancement of Medical Instrumentation (AAMI)

Methods (see ANSI/AAMI/ISO 11137 -1:2006 – Ref 4 and ANSI/AAMI/ISO 11137 -2:2006 – Ref 5):

*      Method 1 -using Bioburden information, or

*      Method VDMAX -substantiating use of selected radiation doses of either 15kGy or 25kGy.

Pre-Sterilization Bioburden of APIs, Drug Products, Medical Devices, and Non-Product Items shall be minimized and controlled. The bioburden shall be determined as defined by the radiation dose setting method that is used, and monitored at an established frequency, not to exceed 12 months, defined in a written Site Standard Operating Procedure (SOP).

Dosimeters shall be used during validation studies and routinely to monitor absorbed radiation dose.

Each Batch/Lot of Dosimeters shall be supplied with a Certificate of Analysis (COA) and prior to use shall be:

*      Calibrated; and

*      Approved for use by the contract facility Quality Team.

An Audit of the Dosimeter Manufacturer(s) shall be conducted by the contract facility Quality Team and shall establish the acceptability of the manufacturer’s validation studies, operations, and facilities.

The Irradiation Source shall be monitored for source decay and the performance documented (e.g., process control chart), at least weekly, to ensure that the required dose range is delivered during gamma radiation sterilization.

Instruments and Elements (I/E), including dosimeters, used to monitor or control gamma radiation sterilization processes shall be calibrated according to an approved schedule.

Gamma Radiation Facilities shall have material handling procedures in place that are designed to preclude the mix-up of irradiated and non-irradiated items.

Mixed loads containing more than one batch or lot of material within one irradiation carrier or container are prohibited.

Additional Exposure to Sterilization Conditions or Reprocessing (e.g., as a result of an aborted cycle or mechanical failure) must be approved by the Site Quality Team and supported by validation studies that provide documented evidence that the long-term product stability is unaffected by additional processing. Total exposure shall not exceed the maximum validated limit of the radiation dose.

Irradiator Dose Mapping Studies shall be conducted to characterize the irradiator with respect to the magnitude, distribution, and reproducibility of dose delivery. Irradiator dose mapping shall be performed:

*      On each conveyor path or batch chamber;

*      Using irradiation carriers filled to their design limits with material of a homogenous density (e.g., simulated product or a representative product of uniform density) within the limits of the bulk density range for which the      irradiator is to be used;

*      On representative irradiation carriers to determine the variability of absorbed dose between carriers; and

*      Using dosimeters placed evenly in three (3) planes in a minimum of three (3) carriers.

Load Patterns shall be established and shall include, and not be limited to, the following:

 *    Description of the Primary Packagingand Secondary Packaging of the API, drug product, medical device, or non-product item, including dimensions and density;

*    Orientation of the product or item in the packaging; and

*     Diagram of the load pattern within the irradiation carrier.

Product and Non-Product Item Dose Mapping Studies shall be performed on each load pattern to identify the zones of minimum and maximum dose and to assess the reproducibility of the process. Product and non-product item dose mapping shall be:

*     Performed at the limits of the density ranges of the items to be processed;

*     Performed using dosimeters concentrated in areas of minimum and maximum dose within the irradiation carriers;

*     Used to calculate Dose Uniformity; and

*     Used to determine the placement of dosimeters for routine monitoring.

Change Control and Revalidation Measures shall be implemented to identify, document, and review changes that impact validated sterilization systems, including any intended changes to equipment, process, radiation source, API, drug product, medical device, package configuration, or non-product item.

The contract facility management shall notify the Site Quality Team of any intended changes potentially affecting validation. The Site Quality Team shall:

*      Review approved and implemented changes on validated radiation sterilization systems, to determine the impact on the validated state of the sterilization process;

*      Recommend revalidation requirements;

*      Ensure that at least one Performance Qualification (PQ) run is performed annually; and

*      Document the review results.

A Minimum of One Dose Mapping Study of the product or non-product item shall be performed when there are changes that affect the validated state of the sterilizer (e.g., isotope in the source rack is added, removed, or redistributed).

Time Limits shall be established and monitored and include:

* The maximum time interval between completion of manufacturing of the API, drug product, or medical device, or the preparation of the non-product item for sterilization and the start of the sterilization process; and

* The maximum time interval for the irradiation sterilization process.

Sterilization Dose Audits shall be:

* Performed to confirm the validity of the sterilization dose;

* Conducted at a frequency based on documented rationale, not to exceed twelve (12) months provided at least one lot is irradiated during that period; and

* Performed following any change that could affect the level or nature of the indigenous bioburden.

Rationale for Dose Audit Frequency, if frequency is greater than three (3) months, shall include consideration of the following:

* Bioburden limit;

* Bioburden resistance information;

* Method used to establish the sterilization dose;

* Materials being sterilized (e.g., natural or synthetic source);

* Manufacturing environment; and

* Material handling controls.

Method 1, Dose Audits shall be conducted according to ANSI/AAMI/ISO 11137-1:2006 (Ref 4):

* Obtain a random sample of one hundred ten (110) product units and determine the bioburden on ten (10) of the sampled units;

* Irradiate the remaining one hundred (100) product units at the Verification Dose used in the original dose setting experiment to establish the radiation dose;

* Determine the dose delivered to the product units and verify that the highest dose delivered is not more than ten (10) percent of the verification dose;

* Verify that the arithmetic mean of the highest and lowest doses delivered to the product units are not less than ninety (90) percent of the verification dose;

* Sterility test each irradiated unit and determine the number of positive units;

* If there are no more than two (2) positive sterility tests from the one hundred (100) sterility tests performed, then the original sterilizing dose is acceptable; or

* If the number of positive units is greater than two (2), then an investigation must be completed per AAMI Standard 11137-2: 2006 (Ref 5) to determine if the sterilization dose must be changed (e.g., as a result of a change in the   product bioburden).

Method VDMAX Dose Audits shall be conducted according to ANSI/AAMI/ISO 11137-1:2006 (Ref 4):

* Obtain a random sample of twenty (20) product units from a single batch;

* Determine the bioburden on ten (10) of the sampled units and calculate the average bioburden;

* Irradiate the remaining ten (10) product units at the verification dose used in the original dose setting experiment to substantiate the radiation dose;

* Determine the dose delivered to the product units and verify that the highest dose delivered does not exceed the verification dose by more than 0.1kGy or more than ten (10) percent, whichever is greater;

* Verify that the arithmetic mean of the highest and lowest doses delivered to the product units is not less than ninety (90) percent of the verification dose;

* Sterility test each irradiated unit and determine the number of positive units;

* If there are no more than one (1) positive sterility tests from the ten (10) sterility test performed then the original sterilizing dose is acceptable;

* If there are two (2) positive sterility tests from the ten (10) sterility tests performed, then a confirmatory sterilization dose audit shall be performed; or

* If the number of positive units is greater than 2, then an investigation must be completed per AAMI Standard 11137-2: 2006 (Ref 5) to determine if the sterilization dose must be changed (e.g., as a result of a change in the product bioburden).

Documented Accountability Measures shall be established to ensure accountability of the product or non-product items through all processing steps, including receipt, loading, unloading, and post irradiation handling and release.

J. Preventing Cross Contamination

This practice document defines the requirements for the prevention of Cross Contamination in Production processes, warehousing, material transfer, and distribution.

Equipment cleaning plays an important role in the prevention of cross contamination

This practice applies to GMP Sites responsible for production, storage, and distribution of Raw Materials (RM), Starting Materials, Intermediates, APIs, In-Process Materials, drug products, Medical Devices, or Biologicals.

Operations shall be conducted in a manner that prevents cross contamination of RMs, starting materials, intermediates, APIs, in-process materials, drug products, medical devices, and biologicals.

Facilities, Utilities, and Equipment shall be designed, constructed, used, and maintained in a manner that minimizes the potential for cross contamination, including consideration of, and not limited to, the following:

* Contamination risks from outside air, including exhaust from Site facilities and other industrial activities in the vicinity;

*Materials of construction for buildings and installations;

* HVAC systems;

* Water systems; and

* Drainage systems.

Materials and Products shall be handled in a manner designed to prevent uncontrolled release of dust, gases, vapours, sprays, or microorganisms into the production environment.

Standard Operating Procedures (SOP) shall be established at each Site to minimize cross contamination and shall address, and not be limited to, the following items:

* Material storage and flow;

* Sampling;

* Personnel gowning, practices, and flow;

* Cleaning and line clearance;

* Handling of spills;

* Equipment usage, storage, and flow; and

* Environmental requirements (e.g., dust, microorganisms, Pressure Differentials, airflow).

Special Containment Measures, such as Special Precautions, Dedicated Manufacturing Suites, or Dedicated Manufacturing Facilities shall be taken to prevent cross contamination where trace presence of one product [e.g., Occupational Exposure Band (OEB) classification 4 or classification 5 products, beta-lactams, and Cytotoxics] could have serious consequences on patients taking another product. This policy does not apply to facilities that are dedicated to animal health products.

Live Microorganisms and Biological Preparations shall be manufactured, transferred, sampled, and packaged in closed or contained systems in separate or defined areas to prevent cross contamination.

Personnel shall not pass through areas, where exposure to live organisms or animals is possible, to access Production Areas where other exposed products or different organisms are handled. If such passage is unavoidable, clearly defined decontamination measures shall be followed, including changes of clothing and shoes and, where necessary, showering.

Centrifugation and Blending of Products Containing Live Microorganisms, which can lead to aerosol formation, shall be contained to prevent release of live microorganisms.

Delivery, Receipt, Sampling and Testing of Bulk Materials (e.g., Tankers Delivery) shall be performed according to SOPs designed to minimize cross contamination.

Product Changeover Cleaning Procedures must be Validated Pesticides and Herbicides shall not be produced or stored in the same facilities as those used for the manufacture and storage of APIs, intermediates, in-process materials, drug products, or medical devices.

K. Control of Manufacturing and Packaging Defects Non-Sterile

Non-Sterile Drug Products and Non-Sterile Medical Devices shall be inspected for manufacturing and packaging defects and general appearance by Qualified personnel authorized by the Site Quality Team.

This practice defines the requirements for the following:

–     Detection of defects by inspection systems; Inspection to cull known defects; and Inspection for defects for Lot acceptability.

–     Systems and Controls shall be developed and implemented at each Site for the detection of manufacturing and packaging defects for non-sterile drug products and non-sterile medical devices manufactured or packaged at the Site.

–    Inspections for Defects shall be performed by qualified personnel at key defined stages of manufacturing and packaging based on Approved statistical inspection and sampling plans.

–    Any Medical Condition shall be reported to the supervisor. The individual shall not perform inspections until the condition is corrected or medically cleared.

–    Manufacturing and Packaging Defect Categories shall be established and shall include:

*      Critical Defects,

*      Major Defects, and

*      Minor Defects.

–    Actions that must be taken when critical, major, or minor defects are encountered during the inspection process (e.g., segregation of defective product or increased sampling) shall be written and approved by the Site Quality Team.

–    Inspection for Manufacturing and Packaging Defects shall include one or more of the following methods:

*Human visual inspection; and

*Automated electronic inspection system or line monitoring devices.

–     An Acceptable Quality Level (AQL) shall be established for each defect category (i.e., critical, major, and minor) for each product. The AQL for critical defects shall be 0.01 percent.

–     An Investigation shall be conducted and documented when the number or percent of defects exceeds the AQL. The investigation shall be documented in a Quality Deviation Report.

–     Manufacturing Defects shall be documented and Trended for each product.

–     Packaging Defects shall be documented and trended for each finished product. Consideration shall be given to trending packaging defects according to the Container/Closure configuration (e.g., tablets in a bottle or tablets in a blister card), and finished packaging configuration (e.g., carton of 10 blister cards or package of 30 blister cards).

–     Product that has been Involved in an Unusual Event (e.g., expanded visual inspection due to a product defect) shall be segregated from the restof the lotor Batch and only returned to the rest of the lot or batch after investigation, and approval by the Site Quality Team. The investigation may include additional or special inspection of the product. The investigation shall be documented in a deviation report.

–     Samples Removed from the Defined Production Area During a Process shall not be returned to the lot or batch.

–     At the Completion of Packaging Operations, representative samples of the finished product collected during the packaging operation shall be visually examined for correct Labeling and the results of this examination recorded in the batch Record or Device History Record (DHR).

–     Automated Electronic Inspection Systems shall be Commissioned and Qualified

–     Proper Operation of Automated Electronic System Inspection Equipment and Line Monitoring Devices shall be Verified (e.g., use of test sets with known defects) at the beginning and end of each batch or lot and documented in the batch record or DHR.

L. Sterilization/Depyrogenation Validation: Non-Product

This practice document establishes the requirements for Validating Sterilization and Depyrogenation of equipment, and Containers and Closures with direct or potential contact with Sterile Medical Devices, sterile Drug Products, or sterile Active Pharmaceutical Ingredients (API). The methods discussed include sterilization using steam or ethylene oxide (EtO), and sterilization/depyrogenation using dry heat (DH).

This practice applies to GMP Production Sites where equipment, containers, and closures with direct or potential contact with sterile medical devices, sterile drug products, or sterile APIs are sterilized and/or depyrogenated for Pharmaceutical or Animal Health.

Sterilization and Depyrogenation Studies shall be performed following the site specific validation requirements.

The Overkill Sterilization Approach shall be used unless there is documented evidence that the sterilization method has an adverse effect on the material.

Heat Stable Items Sterilized with Saturated Steam shall demonstrate a minimum F0  of fifteen (15) minutes. Dry Heat Sterilization Overkill Cycles shall demonstrate a minimum FH of thirty (30) minutes. Annual Sterilizer Requalification Requirements shall include, at a minimum, conducting Performance Qualification (PQ) studies using representative load patterns to Verify performance of the sterilizer.

Sterilization/Depyrogenation Systems shall be subject to a Preventive Maintenance (PM) program.

Instruments and Elements (I/E) Used to Validate, Monitor or Control Sterilization/Depyrogenation Processes shall be Calibrated according to an Approved schedule.

The Sterilization and Depyrogenation Processes must not have an adverse effect on the materials being sterilized and/or depyrogenated.

Materials Used in Sterilization Processes, such as EtO gas shall be received in the same manner as Raw Materials (RM).Testing and/or inspection and release requirements for these materials shall be defined in written and approved Specifications.

Suppliers of Biological Indicators (BI) and Endotoxin Indicators (EI) shall be accepted only after an audit has been conducted that establishes the acceptability of their validation studies, operations, and facilities. The audit report shall be approved by the Site Quality Team. Biological Indicators (BI) shall be used as follows during the validation of sterilization cycles:

* BIs shall be placed adjacent to thermocouples and in the load during sterilization validation studies to provide a challenge to the sterilization process that exceeds the challenge of the indigenous Bioburden;

* BIs must be completely inactivated under proposed sterilization cycle conditions;

* Minimum acceptable FBiovalue  of twelve (12) minutes in relation to the production cycle; and

* BI Survival Time and Kill Time(i.e., Thermal Resistance Window) must be known for the conditions that will be used during Site validation studies. Corporate Environmental Health and Safety (EH&S) Guidelines for use, handling, and monitoring of EtO gas shall be followed.

Sterilizer Commissioning and Qualification shall be performed. In addition, filters shall be Integrity Tested.

Critical Process Parameters (e.g., temperature, exposure time) for each type of sterilization or depyrogenation method shall be identified, monitored, and controlled by calibrated I/Es traceable to a standard (e.g., NIST).

Limits for critical parameters shall be established and monitored for each phase of the sterilization/ depyrogenation cycle. Failure to meet the established limits or specifications shall result in an invalid run and require an Investigation.

For Static, Batch Type Sterilizers, Thermocouples shall be placed uniformly throughout the chamber and load, including the Slowest-To-Heat Zone, during Operational Qualification (OQ)/PQ runs.

Each Lot of Commercially Prepared BIs shall have a Certificate of Analysis (COA) from the manufacturer.

Custom Prepared BIs for Moist Heat Sterilization or dry heat sterilization shall be tested prior to use for:

*      Spore population; and

*      D-value.

When BI Spore Suspensions are Directly Inoculated onto Components (e.g., Closures) or Equipment for moist or dry heat sterilization, the D-value must be tested after inoculation of the spore suspensions onto the substrate.

Steam Sterilization Critical Process Parameters shall include temperature, pressure, and exposure time.

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

Steam Sterilization Cycle Development shall include the following:

*  Verification of steam saturation using a temperature/pressure correlation table;

* Calculation of F0 in the coolest location in the load (from temperature mapping studies) to determine the degree of lethality as a function of Process Parameters;

For Steam Sterilization Processes, if load probes are present in the sterilizer, the placement of the probes shall be established during validation studies and the data generated during a run shall be reviewed against specifications.

Vacuum Leak Tests shall be conducted during qualification studies on steam sterilizers and included in the PM program.

The Bowie Dick Test (e.g., see ANSI/AAMI/ISO 11134: 1993 – Ref 10) or equivalent shall be performed on steam sterilizers that use vacuum cycles, at least quarterly, to ensure that the specified vacuum is achieved in the steam sterilization unit.

DH Sterilization and Depyrogenation Critical Process Parameters shall include temperature and exposure time.

DH Sterilization and Depyrogenation Equipment shall be designed and equipped with HEPA filtered air and designed to operate at an overpressure to the surrounding environment for the following types of units:

*      Forced air convection ovens, and

*      Continuous belt dry heat tunnels.

DH Depyrogenation Cycle Development shall include the following:

*      Runs conducted using EIs;

*      Diagram of the placement of EIs; and

*      A three (3) log reduction in Bacterial Endotoxin as demonstrated by Bacterial Endotoxin Testing (BET). EIs for DH Depyrogenation shall consist of the following:

*     Purified lipopolysaccharides (LPS) from gram negative bacteria (e.g., Escherichia coli) such as Control Standard Endotoxin (CSE) that has been characterized against a current Reference Standard Endotoxin (RSE) to prepare a concentrated solution of endotoxin;

*      Use a carrier material that is the same as the item to be depyrogenated or as resistant to the depyrogenation process;

*      Inoculate the carrier (e.g., glass vial) with the smallest volume of endotoxin solution that will ensure a detectable three (3) log reduction (e.g., 0.1mL of an endotoxin solution at 100,000 EUmL); and

*      Ensure that the EIs are fixed to the carrier by a method such as air-drying.

Note: CSE is equivalent to a Working Reference Standard and RSE is equivalent to a Master Reference Standard.

Qualification of EIs for Dry Heat Sterilization shall include, and not be limited to, the following:

*      Determination of expected recovery efficiency; and

*      Demonstration of storage stability.

EtO Sterilization Critical Process Parameters shall include temperature, relative humidity (RH), pressure, gas concentration, and exposure time.

EtO Sterilization Cycle Development shall use the Half-Cycle Approach and include the following:

*      Verify the jacket temperature is controlled within +/-3oC of the set point;

*      Determine temperature and RH parameters (i.e., Preconditioning) for the material to be sterilized;

*      Determine sterilization and aeration parameters;

*      Conduct runs using Multi-Parameter Process Indicators placed throughout the load to verify the concentration of EtO and uniformity of RH and temperature; and

*      Determine the minimum degassing hold times and maximum permissible residual levels for EtO, ethylene glycol, and ethylene chlorohydrin.

The EtO Sterilization Cycle shall include air removal by vacuum and/or displacement with an inert gas (e.g., nitrogen);

Materials Sterilized by EtO shall be degassed for a validated period of time in a heated, ventilated area prior to use. The acceptable levels of EtO residuals shall be determined during validation.

M. Gowning Practices for Aseptic Processing Areas and Preparation for Aseptic Areas

This practice document defines the gowning requirements for Aseptic Processing Area (APA) Personnel, APA Support Personnel, Preparation for Aseptic Areas (PAA) Personnel, and PAA Support Personnel.

This practice applies to GMP Production Sites performing aseptic operations for Sterile Active Pharmaceutical Ingredients (API), sterile Drug Products, Biologics, or sterile Medical Devices for Pharmaceutical or Animal Health.

Personnel Performing Job Functions that have Direct or Indirect Impact on Aseptic Processing shall wear protective clothing (i.e., secondary garment) to prevent Viable and Non-Viable Particulate contamination of equipment, Containers, Closures, In-Process Materials, Intermediates, APIs, drug products, and/or medical devices prior to and following Sterilization and use in an APA.

Personnel Known or Observed to have an apparent illness or open lesions (as determined by medical examination or supervisory observation) shall be reassigned to work outside the APA and/or PAA until cleared either by medical examination or supervisory observation.

A Clean Uniform and Area-Dedicated Shoes shall be put on daily by APA Personnel, APA Support Personnel, PAA Personnel and PAA Support Personnel prior to putting on the secondary garment(s) applicable to the area (APA or PAA).

Visiting Personnel shall be provided special instructions by, and gowned under, direct supervision of a Qualified APA colleague prior to entering the APA or by a qualified PAA colleague prior to entering the PAA.

Visiting personnel shall be escorted by a qualified colleague at all times while in the APA and/or PAA. Visiting personnel shall put on a clean uniform and shoe covers prior to entering either the PAA or APA.

Powder-Free Gloves shall be worn at all times by PAA Personnel when preparing (e.g., cleaning, wrapping) equipment, containers, and closures for sterilization.

Sterile, Clean APA Gowning Articles shall be put on for each entry into the APA, including wearing of sterilized goggles over the eyes. Cleaning and sterilization of gowning articles shall be Validated.

Used APA Gowning Articles shall be deposited in designated containers in the degowning room. Used APA gowning articles shall be removed, at least, once per day from the area. Containers of used gowns shall not be allowed to be over-filled.

Gown and Glove Monitoring for Microbial Contamination for APA Personnel and APA Support Personnel shall be performed as. An Investigation shall be conducted when APA Personnel and APA Support Personnel exceed established gown or glove monitoring Action Levels.

In the Event of a Facility Evacuation (e.g., fire drill), APA Personnel, APA Support Personnel, PAA Personnel and PAA Support Personnel shall, upon returning to the building after evacuation, re-gown prior to reentering the APA or PAA following the gowning procedures defined in this practice. When area-dedicated shoes are worn outside of the building, shoe covers shall be worn over area-dedicated shoes until the area-dedicated shoes can be Disinfected or replaced with another pair of area-dedicated shoes.

APA Personnel, APA Support Personnel, PAA Personnel, or PAA Support Personnel with an apparent illness or open lesion shall contact the responsible APA or PAA

Supervisor for reassignment outside of the APA or PAA. Illnesses (as determined by medical examination or supervisory observation) that shall preclude entering the

APA or PAA include, and are not limited to, the following:

* Upper respiratory infections;

* Gastrointestinal infections;

* Influenza; and

* Skin conditions (e.g., severe sunburn, psoriasis, open sores).

Visiting personnel with an apparent illness or open lesion shall not enter the PAA or APA.

Personnel Working or Visiting Personnel in the APA or PAA shall:

* Practice good hygiene, as outlined during training;

* Not wear jewelry, except for a smooth wedding band;

* Not wear makeup;

* Not wear false eyelashes;

* Minimize facial hair;

* Cover hair completely with hair covers (including facial hair);

* Keep nails short, not wear nail polish, and not wear artificial nails; and

* Wear goggles in APA, or eye protection (e.g., safety glasses with side shields) in PAA.

APA Gowns shall be made of non-linting and non-static producing material. Sterilized gowning articles shall be packaged in non-shedding, non-cellulose packages.

PAA Secondary Garments shall be made of non-linting and non-static producing materials with elasticized wrists such as a clean lint-free lab coat or disposable garment (e.g., Tyvek). -Studies shall be conducted to demonstrate the number of times reusable gowns can be cleaned and sterilized, if applicable, before being discarded. A system for tracking the number of gown cleanings and sterilizations shall be implemented.

Gowning and Degowning for the PAA shall be performed in a gowning/degowning room adjacent to the PAA. Fresh, protective clothing shall be stored neatly in bins and/or on racks. The PAA gowning/degowning room shall be equipped with a bench and hand-washing facilities or a dispenser containing sanitizer. Gowning for the PAA shall be performed as follows:

a) Put on fresh shoe covers over area-dedicated shoes. Visiting personnel shall put on a second pair of shoe covers over the original shoe covers;

b) Wash and dry hands or use sanitizer from dispenser;

c) Cover hair completely (including facial hair) with fresh hair covers;

d) Put on a secondary garment; and e) Put on eye protection.

In the Event of a Glove and/or Secondary Garment Tear, PAA Personnel or PAA Support Personnel shall replace the torn article.

PAA Personnel, PAA Support Personnel, and PAA Visiting Personnel shall degown as follows upon exiting the PAA:

* Place eye protection in the designated storage rack in the gowning/degowning area for use upon reentry;

* Hang secondary garments in the gowning/degowning area for reentry;

* If no reentry is planned, place reusable, secondary garments in the laundry container;

* Dispose of single use garments (e.g., gloves, disposable garments); and

* Dispose of used hair and shoe covers prior to exiting the building.

Secondary garments (e.g., lint-free lab coats or disposable garments) must be replaced once a shift.

APA Hand Sanitization Area Practices shall be in accordance with the following sequence:

a) Ensure hair, including facial hair, is completely covered;

b) Put on fresh shoe covers over area-dedicated shoes. Visiting personnel shall put on a second pair of shoe covers over the original shoe covers;

c) Disinfect (e.g., with povidone-iodine solution, alcohol foam) hands and arms to the elbows and air dry; and

d) Avoid touching any unsanitized or non-sterile surface after disinfecting and drying.

Gowning for the APA shall be performed in a gowning room adjacent to the APA and shall follow a validated gowning sequence, for example:

a) Put on sterile powder-free gloves;

b) Disinfect gloves after every step or if any surface is inadvertently touched;

c) Put on sterile boot covers one at a time while stepping over the bench room divider and do not allow a booted shoe to touch a non-aseptic zone;

d) Select a correctly-sized sterile garment and verify sterilization status and Expiration Date;

e) Put on sterile hood;

f) Put on sterile mask;

g) Put on a sterile garment, ensure hood is tucked into the gown and ensure that boot covers are secured over the elasticized legs of the garment;

h) Put on sterilized goggles;

i) Put on a second pair of sterile powder-free gloves; and

j) Inspect gowning articles for correct application in full-length mirror before proceeding to the APA.

The Maximum Number of Personnel in the aseptic gowning room shall be established and supported by validation studies.

In the Event of a Gown or Glove Tear, APA Personnel and APA Support Personnel shall proceed as follows:

* Gown tear or inner glove tear resulting in tearing of the outer glove: leave the APA via the APA degowning room. To reenter the APA enter through the gowning area and follow all entry procedures; or

* Outer glove tear: return to the gowning room, remove outer gloves, disinfect gloved hands, put on a new pair of sterile gloves, and disinfect gloved hands.

APA Personnel and APA Support Personnel Gown and Glove Monitoring shall be performed by qualified personnel authorized by the Site Quality Team. The practice of unobserved self-sampling is not allowed.

An Investigation shall be conducted and documented when APA Personnel and APA Support Personnel exceed established glove or gown monitoring action levels. Potential follow-up actions include, and are not limited to:

*      Increased sampling,

*      Increased observation,

*      Retraining,

*      Gowning requalification, or

*      Reassignment of the individual to operations outside of the APA.

Unless The Investigation Reveals Another Possible Source, APA Personnel and APA Support Personnel Failing Gown or Glove Monitoring Action Levels during two (2) consecutive tests or three (3) times during a four (4) week period shall be reassigned to work outside of the APA until they have:

* Reviewed the gowning procedures [e.g., Standard Operating Procedure (SOP),video];

* Been retrained in gowning;

* Demonstrated satisfactory gowning techniques to a qualified APA representative; and

* Successfully repeated gowning qualification consecutively on three (3) separate days.

Individuals who continue to fail gown or glove monitoring action levels after retraining as described above shall be evaluated by the Site Quality Team and a decision made regarding whether the individual will be allowed to continue to work in the same capacity in the APA.

PAA Gowning/Degowning shall be performed in a dedicated area in the PAA. Fresh, secondary garments shall be stored neatly in bins and/or on racks. The dedicated PAA gowning/degowning area shall be equipped with a bench and dispenser containing sanitizer.

Hooks for secondary garments that will be reused during a shift shall be located in the dedicated area in the PAA. Laundry containers for used reusable, secondary garments

and waste containers for used powder-free gloves, disposable garments, shoe covers, and hair covers shall be located outside of the PAA.

N. Cleaning Depyrogenation and Sterilization of Containers and Closures

This practice document establishes the requirements for cleaning and Sterilization processes for Containers and Closures used to package Sterile Drug Products and Medical Devices. In addition, this practice addresses Depyrogenation of containers and closures used to package Parenteral drug products.

Containers and Closures that Contact Parenteral Drug Products shall be cleaned in a controlled area using a Validated process that removes particulates.

Containers and Closures that Contact Sterile Drug Products or Sterile Medical Devices shall be sterilized using a validated sterilization method. An Overkill Sterilization method shall be used unless there is documented evidence that the sterilization method has an adverse effect on the material.

Containers and Closures that Contact Parenteral Drug Products shall be depyrogenated using a validated process that assures a minimum three log reduction in Bacterial Endotoxins.

Equipment for Cleaning, Sterilization, and Depyrogenation of Containers and Closures shall be Commissioned and/or Qualified.

Empty Glass Vials, Bottles, and Ampoules that have been through a full dry heat sterilization cycle shall not be recycled for subsequent sterilization of the empty containers. The maximum allowable time that containers and closures are held at sterilization or depyrogenation conditions shall be established and validated.

The Maximum Allowable Number of Times that Rubber Stoppers can be sterilized shall be validated to include effects on:

*The physical and chemical properties of the elastomer; and

*The Container Closure System integrity and product stability.

Containers, Closures, Cleaning Agents, and Silicone Fluid shall be received in the same manner as Raw Materials. Inspection and/or testing and release requirements for these materials shall be defined by Specifications.

Materials Such as Silicone Fluid and Cleaning Agents used in connection with containers and closures prior to sterilization shall be controlled to minimize microbial, particulate, and endotoxin contamination.

The Pre-Sterilization Bioburden of Containers and Closures shall be controlled to a consistently low level when non-thermal processes are used for sterilization (e.g., radiation, ethylene oxide).

Manufacturers and Suppliers responsible for washing and/or sterilizing containers and closures shall be approved following the supplier approval process.

The Maximum Time Interval Allowed Between Washing and Sterilization of containers and closures and the maximum time interval allowed between sterilization and use of the containers and closures shall be validated.

The Flow of Sterile Containers and Closures into the Aseptic Processing Area (APA)shall be unidirectional. Sterile containers and closures shall be delivered to the APA in a manner designed to prevent contamination, such as through double-sided Batch sterilizers, continuous sterilization/depyrogenation tunnels, or Airlocks.

Measures to Differentiate sterile containers and closures from non-sterile containers and closures shall be defined; examples of these measures include:

*Supplier identification of sterile items,

*Sterilization indicators,

*Facility design, and

*Procedures for handling containers and closures before and after sterilization.

Cleaned Containers and Closures shall be protected from contamination prior to sterilization.

Sterilized Packaged Containers and Closures shall be visually inspected for damage to the package prior to storage or use.

Personnel Washing and Sterilizing Containers and Closures shall be Qualified and follow the gowning practices for Preparation for Aseptic Areas (PAA) personnel.

Cleaning, Depyrogenation, and Sterilization Activities shall be documented and the Records retained as part of the batch records.

Containers and Closures shall be protected from particulate contamination by non-shedding protective wrap (e.g., plastic shrink-wrap) that will be removed immediately before cleaning.

Container and Closure Cleaning shall be documented and reviewed as part of the batch records. Documentation shall include, at least, the following:

*Container or closure Batch Number or Lot Number;

*Description of container or closure;

*Final product batch or lot number;

*Date and time of cleaning;

*Identification of the person performing the cleaning;

*Critical Process Parameter limits and actual results; and

*Wash cycle number.

Final Rinsing of Containers and Closures shall be performed in an environment with a minimum Air Classification of Grade D. Cleaned containers and closures shall be handled in a manner designed to prevent contamination.

Washed Containers and Closures shall be protected from particulate and microbial contamination by maintaining at least a Grade D environment for the following areas and activities:

*At the discharge point from the cleaning equipment;

*While loading into trays that will be covered or bags that will be sealed prior to transportation and subsequent sterilization and/or depyrogenation; and

*Between the vial washer and the continuous sterilization/depyrogenation tunnel.

Containers and Closures that are Cleaned with Water shall be washed and rinsed using water of approprizate quality, or recycled and filtered Water For Injection (WFI) from earlier wash stages. Fresh WFI must be used for the final rinse in the cycle.

On Line Cleaning of Sterile Plastic Ophthalmic Containers shall be achieved using a combination of sterile compressed gases (air or nitrogen) and vacuum directed to the inside of the container to remove particulates. Compressed gases used in this manner shall be passed through a microbial retentive filter at the point-of-use. The microbial retentive filters shall be Integrity Tested and have established and documented replacement schedules.

Critical Process Parameter Values (e.g., time, temperature, pressure, or belt speed) shall be recorded during cleaning and sterilization and must fall within validated ranges. Instruments and Elements (I/E) on equipment shall be Calibrated according to an Approved schedule.

Container and Closure Washing Equipment shall include, and not be limited to, the following:

*Stainless steel construction;

*Sanitary fittings and valves;

*Properly sloped pipelines to allow for complete drainage;

*Provisions to ensure that critical process parameters are met for the validated process;

*Critical process parameter (e.g., temperature, pressure) monitoring;

*Recirculated water systems maintained at the required temperature;

*Provision for final rinse to be with fresh (i.e., non-recycled) WFI;

*Sample ports on the supply lines; and

Automatic shut off devices if the critical processing parameters are not met. In lieu of automatic shut off devices, critical processing parameters shall be measured and evaluated in real-time and responses made that are based on approved Standard Operating Procedures (SOP).

After Cleaning, Containers and Closures shall be further processed within the specified time frame and under conditions established during validation that preclude Foreign Matter and bacterial endotoxin contamination.

The Cleaning Cycle for Glass Vials, Bottles, Closures, and Ampoules shall include:

*Equipment designed to wash the inside and outside of the container;

*Final rinse with fresh (i.e., non-recycled) WFI; and

*Removal of excess water (e.g., using filtered, compressed air and/or inversion).

Dry Heat Depyrogenation Equipment Used to Process Glass Vials, Bottles, Closures, and Ampoules shall include and not be limited to:

*Validated capability to reduce bacterial endotoxin levels by at least three logs;

*Stainless steel construction;

*Temperature sensors;

*Belt speed sensors for continuous belt tunnels;

*HEPA Filtered air and airflow sensors;

*Recording devices to document critical processing parameters during a cycle; and

*Automatic shut-off devices if the critical processing parameters are not met. In lieu of automatic shut off devices, critical processing parameters shall be measured and evaluated in real-time and responses made that are based on approved SOPs.

The Cleaning and Depyrogenation Cycle for Rubber Closures shall include:

*Processing cycles capable of a three log reduction in bacterial endotoxins and the removal of excess silicone and particles;  Washing with Purified Water (PW) or equivalent (including Clean Steam, if needed); and  Final rinse with fresh WFI.

Rubber Closures shall be sterilized using clean steam according to a validated cycle.

Each Carrier (e.g., Cart, Basket, Tray, or Plastic Bag with Breather Panel) of Containers and Closures that are Batch Sterilized shall be clearly labeled (e.g., with a non-shedding label such as Tyvek or a metal tag) with the following information:

*Container or closure lot number;

*Sterilization batch or cycle number;

*Date of sterilization; and

*Sterility Expiration Date. Sterilized carriers shall be separated and clearly differentiated from non-sterilized carriers.

Container and Closure Sterilization Processing shall be documented and included in batch records and shall be reviewed by the Site Quality Team for compliance with established and validated limits. Documentation shall include:

*Date and time,

*Name of the person loading the sterilizer,

*Critical process parameters limits and actual results,

*Description of sterilizer load, and

*Sterilization batch or cycle number.

Covered, Sealed, Sterile Containers and Closures Sterilized in Autoclaves or Ovens as a Single Load shall be unloaded and stored in at least a Grade B environment for a period not to exceed the maximum specified validated time interval.

Packaged Sterilized Containers and Closures shall be visually inspected for dryness and package integrity prior to being placed in the APA processing or storage room. Any torn, compressed, wet, or punctured package shall be labeled as damaged and removed from the APA.

Containers and Closures that have been Sterilized by Ethylene Oxide (ETO) Gas shall be unloaded from the sterilizer by qualified personnel following Environmental

Health and Safety (EHS) guidelines for protective equipment. The sealed, sterile containers and closures shall be placed in at least a Grade B environment.

Sterile Containers and Sterile Closures Purchased from a Supplier shall, at a minimum, be triple bagged and shall include a certification of sterilization including ETO residual levels if applicable.

O. Sterilizing Filters and Filtration Systems

This practice document applies to Sterile Filtration applications (e.g., Sterilization of gases, liquids, Solvents, and solutions) used in the manufacture of sterile Active Pharmaceutical Ingredients (API), sterile Medical Devices, and sterile Drug Products.

This practice applies to GMP operation dite where sterile APIs, sterile drug products, and sterile medical devices are produced for Pharmaceutical and Animal Health.

Validation of Filtration Systems which contact sterile APIs, sterile medical devices, sterile drug products, or sterile solvents and gases shall be performed for each product, process, and filter type after process validation requirements are met.

The Type and Number of Sterilizing Grade Filters and Pre-Filters shall be based on the application. Vent Filters shall be Hydrophobic and provisions must be made to eliminate any condensate.

Membrane Filters with a porosity no greater than a nominal 0.22 micron shall be used as sterilizing filters. In cases where microorganisms are not retained by 0.22 micron filters, 0.1 micron filters shall be used (e.g., Mycoplasma sp.).

Pre-filtration Bioburden of Sterile APIs, Sterile Medical Devices, and Sterile Drug Products shall be determined using a Validated Test Method (TM),monitored, minimized, and controlled.

Steam Sterilization Cycles for Filters, in situ, shall be validated using thermocouples and Biological Indicators (BI) located on the upstream and downstream sides of the filter. Steam sterilization cycles for filters sterilized in autoclaves shall be conducted.

Asbestos Containing Filters must never be used.

Sterile Filtration of APIs, drug products, medical devices, compressed gases, and solvents through the Final Filter shall be driven by positive pressure. Vacuum driven filtration shall not be used for sterilization except for use of vent filters.

The Maximum Use Interval for a Sterilizing Filter, in terms of days in use, sterilization cycles, or the number of Batches/Lots processed, must be validated if the filter is to be used in manufacture of sterile APIs, drug products, medical devices, or in sterilizing water or other solvents. When the validated limit is reached, the filter must be replaced.

Sterilizing Grade Filters shall be Integrity Tested and the integrity test (e.g., Bubble Point, Pressure Hold, Forward Flow, Water Intrusion) shall be correlated with microbial retention.

Vent Filters shall be integrity tested before and after use and shall be replaced based on the use period established during validation.

Automated Integrity Test Systems shall be validated.

Specifications shall be established for sterilizing filters and the filters Verified against these specifications prior to use. The verification shall be documented.

Third Party Validation Reports (e.g., Filter Manufacturer) shall not be accepted until an audit has been conducted that establishes acceptability of the validation program.

The Site Quality Team and the Site Production Team shall Approve and accept the audit report and assume responsibility for tracking any corrective actions.

A Contract with a Filter Manufacturer or Filter Supplier shall include a written agreement that no changes to the filter composition or configuration shall be made without first notifying the site purchaser(s). The Validation Committee (VC) shall determine Revalidation requirements for changes to the filter composition or configuration.

Process Stream Sterilizing Filters shall not be reused in a subsequent Campaign for an API or a subsequent lot for a drug product or medical device.

Changes to the Filtration System or Process shall be evaluated using a documented Risk Assessment to determine the need for revalidation.

Selection Criteria for Sterilizing Filters shall include:

*Process stream compatibility;

*Low extractable levels;

*Absorption of active, drug, or other components;

*Method for sterilizing the filter;

*Integrity test method (TM) and criteria;

*Bioburden retention characteristics;

*Sizing of the system to achieve intended flow rates; and

*Maximum allowable Pressure Differential.

A Filter Data Package shall be obtained from the filter manufacturer and shall include, and is not limited to, the following information:

*USP Biological Reactivity Test results (in vivo);

*Extractable testing;

*Bacterial retention testing in water or solvent;

*Differential pressure limits;

*Operational temperature limits;

*Sterilization temperature limits;

*Integrity testing limit in water or other solutions (e.g., solvents or product solutions); and

*Chemical compatibility testing.

Series Redundant Sterilizing Grade Filters shall be used for sterile filtrations of drug products. Each filter must be tested prior to use. The upstream filter in the series must be tested after each batch/lot or campaign.

The downstream filter is tested if the upstream filter fails integrity testing. Where redundant sterilizing filtration is required by local or product regulation, or product filing claims, both filters must be integrity tested post use.

For Drug Products and Sterile Medical Devices the final sterilizing grade filter shall be in close proximity to the filling line.

Installation Qualification (IQ) for Sterilizing Filters shall include verifying and documenting, at least, the following:

*Filter description (e.g., size, porosity, filter material);

*Filter type (e.g., Hydrophilic, hydrophobic);

*Description of the filter housing and other filtration system components (e.g., o-rings, gaskets, valves);

*Vent filter housing temperature control, if used to prevent condensate; and

*Use of the filter (e.g., process stream, water system, vent filter).

Operational Qualification (OQ) for Sterilizing Filters shall include:

*Evaluation of compatibility of the material to be filtered (API, medical device, drug product, solvent, or gas) with the filter;

*Demonstration that the established integrity test specification can be achieved before and after sterilization;

*Determination of the maximum forward and, if applicable, reverse pressure ratings under the proposed operating conditions;

*Determination of flow rate under proposed operating conditions; and

*Determination of maximum filtration time.

Parameters for Steam Sterilization of Filters shall be defined, be within filter manufacturer recommendations, and be verified during OQ for the following:

a. All steam sterilization processes (e.g., Steam In Place (SIP) and autoclave):

     –      Filter assembly preparation;

     –      Physical setup (e.g., vent valves open);

     –      Maximum allowable sterilization temperature and pressure;

     –      Cumulative exposure time at temperature for each sterilization cycle; and

     –      Maximum number of times a filter or filtration

            system can be steam sterilized;

b. In addition to the above, the following items shall also be verified for filters that are autoclaved:

     –      Orientation (e.g., filter in upright position);

     –      Removal of air from the filter and housing, using vacuum purges or flushing with steam; and

     –      Cycle that ensures the filter is completely dry at the end of sterilization for hydrophobic filters.

Product Specific Compatibility Studies shall be conducted for OQ and include, and not be limited to:

*Determine pre-use flush volume of the API, drug product, medical device, or solvent required to flush particles and extractables from the filter prior to use;

*Determine pre-flush volume and method to thoroughly wet the filter;

*Chemical compatibility of all system components (e.g., membrane, gaskets, support materials, o-rings) with the API, drug product, medical device, or solvent;

*Evaluation of the tendency of the API, drug product, medical device, or other components to adsorb to the filter membrane;

*Evaluation of particle shedding from the filter;

Evaluation of extractables from the filter and filter components; and

Impact of the product and longevity of use using Production Process Parameters (e.g., product contact time, temperature, flow rate, pH, surface tension, and viscosity).

Integrity Testing Parameters shall be established during OQ using API, drug product, medical device, or solvent as the wetting agent and include:

*Determination of a product specific integrity test specification (note: laboratory scale batches/lots can be used); and

*An integrity test conducted on a minimum of nine (9) filters [three (3) filters from each of three (3) different lots from the filter manufacturer].

Performance Qualification (PQ) for Filtration Systems used to sterilize APIs, drug products, medical devices, gases, and solvents shall include laboratory studies (e.g., filter manufacturer or in-house) to determine, at least, the following:

*Bioburden determination prior to sterile filtration for APIs, drug products, medical devices, and solvents;

*Microbial retention capability; and

*Verification of the filter manufacturer post-use integrity test correlates with total microbial retention.

Laboratory Microbial Challenge Studies shall be conducted for PQ and include:

*A minimum challenge level of 107 cfu per cm2of filter surface area of a challenge organism (e.g., Brevundimonas diminuta);

If the process stream is Bactericidal or Bacteriostatic for the challenge organism, the use of a product placebo or indirect challenge method shall be used and must ensure that the minimum challenge level is achieved; and

*All of the Filtrate shall be captured and tested for total retention of the challenge organism. Pre-filtration Bioburden Specifications for APIs, drug products, medical devices, or solvents shall be established and/or confirmed during PQ, including:

–     Verification that the pre-filtration bioburden specifications are being met by sampling each batch/lot at the start, and again, just prior to the end of each filtration; and

      –     Determination of such bioburden on a minimum of three (3) batches/lots.

PQ for Compressed Gas Sterilizing Filters and Vent Filters shall include data from filter manufacturers that document, at least, the following:

–     Microbial challenge studies; and

–     Correlation of the integrity test with total microbial retention.

Bioburden Levels prior to the sterilizing filter shall be monitored for every batch of liquid sterile drug product, and final phase aqueous sterile API and shall not exceed validated limits. If the bioburden levels exceed the validated limits, an investigation shall be conducted, which includes a documented risk assessment including at least the following:

*Identification of the microorganism(s),

*Assessment of bacterial endotoxin level, and

*Calculation of the total bioburden level for the lot/batch.

Filtration Time shall be monitored for each batch of liquid sterile drug product, and final phase aqueous sterile API to ensure that the validated maximum filtration time is not exceeded. If the validated maximum filtration time is exceeded, an investigation shall be performed to assess the impact on the product.

Integrity Testing conducted on a sterile filter, prior to use, shall be performed in a manner that prevents contamination of the sterile filter and sterile downstream equipment.

Integrity Testing of Liquid Process Filters shall be conducted within a validated time period after use to prevent a false integrity test result due to drying unless the filters are tested in place on the process equipment or the housings are sealed in a manner that retains residual process liquid in the filter and prevents drying between removal from the equipment and integrity testing.

Failure of a Filter Integrity Test shall be Investigated and documented in a deviation report.

A Single Sterilizing Grade Filter is acceptable in lieu of series redundant sterilizing grade filters, provided the following criteria are met:

*The final sterilizing grade filter shall be integrity tested after sterilization (i.e., before filtration of each batch/lot, or before initiation of a campaign);

*The final sterilizing grade filter shall be integrity tested at the completion of the filtration process for each batch/lot, or campaign;

*The bioburden levels prior to the final sterilizing grade filter shall be monitored for every batch/lot of liquid sterile drug product and shall not exceed validated limits unless an investigation, including a documented risk assessment, is performed that scientifically justifies the acceptability of the bioburden levels prior to the single sterilizing grade filter; and

*In the event of an integrity testing failure at the completion of the filtration process for each batch/lot, or campaign, any associated batches/lots shall be Rejected or Reprocessed using a Validated Process that that has been filed with the Regulatory Team, if required.

P. Moist Heat Terminal Sterilization of Aqueous Parenteral Products

This practice document establishes the requirements for Validation and use of Moist Heat Terminal Sterilization Processes used to Sterilize aqueous Parenteral Drug Products.

This practice applies to GMP Production Sites responsible for moist heat terminal sterilization of aqueous parenteral drug products for Pharmaceutical or Animal Health.

Moist Heat Terminal Sterilization Processes shall be validated.

Equipment used to perform moist heat terminal sterilization shall be properly designed, and Commissioned and/or Qualified.

Validation Studies shall be performed for each terminal sterilization process by Qualified personnel and documented.

Suitability of Moist Heat Terminal Sterilization for each Sterile drug product shall be documented.

All Moist Heat Terminally Sterilized Drug Products shall be subjected to a validated terminal sterilization process using an Overkill Sterilization approach unless there is documented evidence that the sterilization process will adversely affect the finished product.

If the Overkill Sterilization Approach Adversely Affects the Product, an alternative sterilization approach [e.g., combined Bioburden/Biological Indicator (BI) and F0 Approach] shall be developed and validated (see Figure 1 and Table 1)\

All Moist Heat Terminally Sterilized Drug Products must meet a Sterility Assurance Level (SAL)of 10-6 .

Instruments and Elements (I/E) used to monitor or control sterilization processes shall be Calibrated according to an Approved schedule.

Drug Products Intended for Moist Heat Terminal Sterilization shall be prepared under conditions described in Table 1.

Pre-Sterilization Bioburden of drug products shall be determined, monitored, and minimized, and shall not exceed the validated limit prior to terminal sterilization.

Material Handling Procedures shall be established to provide a clear means of differentiating products that have been sterilized from those that have not.

Reprocessing of terminally sterilized parenteral product may be performed only when included in the regulatory filing. Reprocessing must be approved by the Site Quality Team and be supported by validation studies that provide documented evidence that the long-term product stability is unaffected by additional thermal processing.

Biological Indicators (BI) purchased from approved Suppliers shall be used in the validation of sterilization cycles as follows:

–    Provide a challenge to the sterilization process that exceeds the challenge of the indigenous bioburden of the product;

–    BIs completely inactivated under proposed overkill sterilization cycle conditions; and

–    BI Thermal Resistance Window (Survival Time/Kill Time) must be documented for the condition(s) under which the BIs will be used.

–     Use of Moist Heat Terminal Sterilization Contract Vendors shall be addressed in a Quality Agreement

Suitability of a Drug Product for Moist Heat Terminal Sterilization shall be based on an evaluation of:

*Early process development compatibility studies;

*Product Accelerated Stability Testingand/or long term stability studies;

*Impact on Container/Closurematerials; and

*Impact on container/closure integrity.

Critical Process Parameters for moist heat terminal sterilization of a drug product shall be:

*Identified (e.g., temperature, pressure, exposure time, F0) and monitored or controlled by calibrated I/Es traceable to a standard (e.g., NIST); and

*Automatically recorded during each phase of the sterilization cycle at a minimum of once a minute. Temperature shall be monitored in Pilot Bottlesor the chamber drain line depending upon the type of cycle control that is used. Critical Process Parameter Ranges shall be identified and monitored.

Heat Stable products sterilized with saturated steam shall be sterilized using a minimum Steam Sterilization cycle of 15 minutes at 121oC. This cycle is theoretically equivalent to an F0 of 15 minutes, or a 15 log reduction of a heat resistant organism having a D-value of one minute, and represents overkill sterilization conditions.

Design Requirements for the Moist Heat Terminal Sterilizer shall include:

*Control and removal of condensate and cooling water;

*Control of temperature, time, pressure, and the rate of change of temperature and pressure;

*Control instrumentation that is independent of monitoring instrumentation and recorder;

*Systems that prevent unauthorized changes to cycle parameters;

*Capacity to measure temperature at multiple locations within the load; and

*Alarms (audible or visual) that indicate component failure or out-of-limit (OOL) conditions.

*The Product Carrier System Used in the Terminal Moist Heat Sterilizer must have an open design (e.g., wire baskets placed on carts with wire screen shelves) to allow uniform steam penetration and heat transfer as well as drainage of condensate and cooling water. This is especially important for Water Spray, Water Immersion, and Steam-Air-Mixturesterilizers.

BIs in One of the Following Forms shall be used in terminal sterilization cycle development and validation:

*Spore suspension added to representative units of the product or simulated product; and/or

*Self contained packaged indicator that includes the spores suspended in the culture medium in a sealed ampoule (only used for submersion in aqueous liquids).

The D-value of all BIs must be verified by the user. When a spore suspension is added directly to product, compatibility of the BI with the product must be documented, and BI thermal resistance characteristics must be determined (e.g., D-value and kill time for the population size used) in product. Product containers in which the spore suspension has been added shall be identified.

Development of an Overkill Sterilization Process shall include the following:

*Determination of BI compatibility with the product when there is direct inoculation of BI in the drug product;

*Studies conducted using BIs (e.g., Geobacillus stearothermophilus, formerly referred to as Bacillus stearothermophilus) which have a known spore population, D-value and kill time;

*Placement of BIs adjacent to each thermocouple in product and throughout the load;

*Thermocouples placed evenly throughout the load, in product vials, and in the chamber;

*Verification that the F0 of the coolest location meets the required minimum F0;

*Incubation of BIs at 55 – 60oC for 7 calendar days or at the temperature and time periods recommended by the BI supplier;

*All BIs are inactivated during the process;

*Studies to determine cooling time and to verify that rapid cooling by chilled water will not compromise process or Product Integrity; and

*The sterilization process has no adverse physical or chemical effect on the finished product.

Development of a Bioburden/BI F0Cycle Based Sterilization Process shall include the following:

*Enumeration and characterization of product pre-sterilization bioburden in final filled containers to include aerobic microbial count and Heat Shock Screening for heat resistant spores;

*The minimum F0required to effect product sterilization (i.e., SAL 10-6);

*Selection of a BI that is more resistant to sterilization than the most resistant product isolate;

*Determination of BI compatibility with the product when there is direct inoculation of BI in the drug product;

*Studies conducted using BIs (e.g., Geobacillus stearothermophilus, formerly referred to as Bacillus stearothermophilus) which have a known spore population, D-value, and kill time;

*Placement of BIs adjacent to each thermocouple in product and throughout the load;

*Thermocouples placed evenly throughout the load, in product vials and in the chamber;

*(Development of a Bioburden/BI F0Cycle Based Sterilization Process continued from prior page)

*Verification that the F0of the coolest location meets the required minimum F0;

*Incubation of BIs at 55 – 60oC for 7 calendar days or at the temperature and time periods recommended by the BI supplier, and calculation of the FBio Value when complete inactivation of the BIs does not occur;

*Studies to determine cooling time and verify that rapid cooling by chilled water will not compromise process or product integrity; and

*The sterilization process has no adverse physical or chemical effect on the finished product.

Validated Sterilizer Load Configurations shall be established for all sterilization processes and shall include, and not be limited to, the following:

*Description of container design, shape, size, and fill volume;

*Description of the type, size, and configuration of the closure and seal;

*Description of minimum and maximum load size;

*Description and diagram of the loading configuration within the chamber;

*Determination of hot and cold spots for each loading configuration;

*Placement of thermocouples and BIs in product containers and throughout the load, described and diagrammed; and

*Documentation of the number and location of thermocouples and BIs used during validation.

The Effects of Loading on Thermal Input to the Product shall be determined with minimum and maximum load configurations. Thermocouples shall be evenly distributed throughout the load in product containers as well as in the chamber. Documentation shall include, and not be limited to:

*High and low temperatures (range) during exposure;

*Come Up Time(range);

*Minimum and maximum product F0;

*Exposure time (range);

*Come Down Time(range);

*Cooling cycle time (range);

*Product name, run date, and time;

*Any alarms that occur during the process; and

*Identification of the autoclave.

Sterilizer Monitoring and Control I/Es shall be calibrated before the Operational Qualification (OQ) study and routinely according to a defined calibration schedule.

External Monitoring and Recording I/Es (e.g., data logger and thermocouples) shall be calibrated before and after the OQ study and before and after the Performance Qualification (PQ)study.

Qualification Studies shall be performed for each product and each container or package size for moist heat terminal sterilization and shall include, and not be limited to:

*Cycle using thermocouples in the chamber and in simulated or actual product;

*Verification of balance between internal head space pressure in the drug product container and the chamber pressure during all phases of the sterilization cycle to preserve container/closure integrity;

*Heat penetration studies for each different load configuration to confirm the Slowest-To-Heat Zone, and Worst Case load configuration;

*Verification that the stopper-cap interface is dry upon completion of the cycle;

*Verification of container/closure integrity before and after sterilization to ensure that the cycle does not cause container/closure integrity failure; and

*Verification of condensate control and removal from the sterilizer jacket, if present.

The Following Qualification Studies shall be performed initially and following significant changes (e.g., change to operating parameters, change to steam supply, change to controller, change to sterilizer location) for moist heat sterilization processes prior to production use:

For a bracketing approach, a minimum of 3 consecutive, successful studies of each of the minimum and maximum load configurations (total of at least 6 studies) using minimum cycle set point parameters (e.g., sterilization temperature and/or time), BIs, and meeting all validation acceptance criteria; and

*A minimum of one successful maximum load study using defined (e.g., nominal) cycle parameters and BIs and meeting all validation acceptance criteria.

Simulated Product Used in Validation Studies shall be of similar physical properties to the actual drug product. Consideration shall be given to simulating Product Attributes including, and not limited to, volume, container size, headspace, density, and viscosity.

Routine Requalification Studies shall be performed for moist heat sterilization on, at least, an annual basis as follows:

*Perform an annual review of approved and implemented changes on validated sterilization systems, including maintenance and calibration, to determine the cumulative impact on the validated state of the equipment and/or process; and

*Ensure that, at least, one successful Worst Case load qualification study is performed annually on each sterilizer.

Preventive Maintenance (PM)Measures for Moist Heat Terminal Sterilizers shall include, and not be limited to, the following:

*Check operation of vacuum pumps;

*Verify integrity of heat exchangers;

*Clean chamber, steam traps, and drains;

*Vacuum Leak Testthe chamber;

*Verify the operation of safety devices;

*Verify that jacket condensate drains properly (e.g., by performing preventive maintenance on the trap and/or use of a sight glass on the jacket); and

*Check door seals and gaskets for deterioration.

Vacuum Leak Tests shall be conducted during qualification studies on moist heat terminal sterilizers that use vacuum cycles, and the leak rate shall not exceed the manufacturer’s Specifications.

Time Limits or Specifications shall be established, validated, and monitored, and shall include the following:

*Maximum time interval between the start of compounding and the end of Filtrationprior to filling for Filter to Hold Operations;

*Maximum time interval between the end of filtration and the start of filling for filter to hold operations;

*Maximum time interval between the start of compounding and the end of filling for Filter to Fill Operations;

*Maximum time interval for completion of filling;

*Maximum time interval between completion of filling and start of sterilization; and

*Maximum and minimum time intervals for the sterilization process.

An Investigation shall be conducted including documentation of the effect(s) on the product(s) when Deviations occur, including and not limited to, the following:

*Failure to meet the established time limits or specifications for sterilization;

*Failure to complete the terminal sterilization cycle;

*Process interruptions during sterilization; and/or

*Any critical process parameter alarm conditions occurring during sterilization.

Operation of Moist Heat Sterilizers and Product Sterilization Parameters shall be described in Standard Operating Procedures (SOP)or Batch/Lot

Record operating instructions and include:

*Description of the sterilization program(s);

*Description of loading pattern(s);

*Thermocouple placement (e.g., pilot bottles, drain line);

*Actions to be taken in response to alarm conditions (e.g., aborted cycles); and

*Review and approval of sterilization cycle records.

Sterilization Records shall be available for each sterilization run and shall be approved as part of the batch release procedure. Each sterilization record shall include, and not be limited to, the following:

*Date;

*Sterilizer identification;

*Cycle type;

*Cycle parameters;

*Description of the loading pattern;

*Description of thermocouple placement in loads (e.g., pilot bottles, drain line);

*Operator identification;

*Minimum and maximum F0;

*Chamber temperatures and pressures throughout the cycle;

*Timing of each cycle phase, including start time, come up, exposure, come down, and cool time;

*Product temperature at completion of cooling phase;

*Accountability of product before and after sterilization; and

*Process interruptions, deviations, and alarm conditions, and any actions taken.

Drug Product Solutions for Terminal Sterilization shall be filtered prior to filling to ensure that the bioburden does not exceed the validated limit prior to terminal sterilization.

Clean Steam shall be used in steam sterilization processes where steam is in direct contact with the Container Closure System.

Water for Injection (WFI)shall be used for water spray, and water immersion heating and cooling processes associated with moist heat terminal sterilization.

A Monitoring Program for product, Raw Materials (RM), components, environment, and process water shall be established and executed to assure that validated and established bioburden limits are not exceeded. The Site Quality Team shall be responsible for

Trending and reviewing the resulting microbiological data.

Routine Monitoring of Product Pre-Sterilization Bioburden shall be established and shall delineate the following:

*Frequency of monitoring;

*Sampling instructions;

*Test methodologies;

*Bioburden acceptance criteria for total aerobic microbial count (Alertand Action Levels);

*Heat shock screening and spore count for products produced under non-aseptic conditions; and Corrective actions.

Results from monitoring shall be considered when reviewing batch documentation for finished product release.

Any Organism(s) Isolated from Product Containers Filled Under Non-Aseptic Conditions shall be heat shock tested (i.e., 100oC for 10 minutes) during product pre-sterilization bioburden screening, if an overkill sterilization cycle is not used. Any isolate that survives the heat shock treatment is a spore former and shall be:

*Grown up as a spore crop;

*Tested for heat resistance (D-value); and

*Compared to the heat resistance of the BI organism used for cycle validation.

The batch is deemed non-sterile if the heat resistance of the isolate exceeds that of the BI organism used for cycle validation, and validation of the sterilization process must be repeated using a more heat resistant organism.

Measures to Differentiate sterile drug product from drug products that have not yet been sterilized shall be defined. Examples of these measures include:

*Sterilization indicators;

*Facility design (e.g., physical barriers); and

*Procedures for handling drug product before and after sterilization.

In addition, each basket, tray, or other carrier of products or components shall be clearly labeled with at least the material name and material Batch Number or Lot Number.

Sampling of the finished sterile drug product shall be consistent with the validated sampling plan and shall be representative of all zones of the sterilization chamber, and include samples from the coolest part of the load.

Each load of terminally sterilized drug product must be sampled for sterility testing unless the sterilization process has been approved for Parametric Release.

The Site Quality Team shall review and approve sterilization records for terminally sterilized drug products prior to the release of the product.

Figure 1: Decision Tree for Sterilization of Aqueous Products

Table 1: Processing Controls for Terminally Parenteral Products

Q. Media Fills for Sterile Drug Products and Aseptically Processed Medical Devices

This practice document establishes the requirements for the performance of Media Fills for Sterile Drug Products and aseptically processed Medical Devices.

This practice applies to GMP Production Sites performing aseptic filling operations for sterile drug products and Biologicals and aseptic processing of medical devices for Pharmaceutical and Animal Health.

Media Fills that simulate actual aseptic operations shall be performed according to an Approved Protocol for:

*Each aseptic filling line;

*Lyophilizer; and

*Each new process (e.g., equipment, filling speed, Filtration) or Container Closure configuration not represented in a previous Performance Qualification (PQ).

Media Fills for Liquid Products and Lyophilized Products shall simulate the process from the point of Sterilization through to the completion of filling, and lyophilization, as applicable, including any aseptic operation performed during the drug product compounding. The media fill simulation shall include any product holding times after the product is considered sterile.

Media Fills for Dry Powder Products shall simulate the process from the point of addition of the product to the filling machine through to the completion of filling, including any aseptic operation performed during the drug product compounding.

Each Aseptic Filling Line shall be re-qualified twice annually for each shift at 5 to 7 month intervals when in use.

Filling Lines shall be re-qualified prior to production use when there have been:

*Significant changes to the line or HVAC system;

*Where the conclusion of an Investigation indicates the need for re-qualification after a confirmed sterility test failure; or

*Where an investigation concludes the pattern or extent of environmental monitoring excursions is sufficiently abnormal to suggest the need for re-qualification. Each occurrence shall be evaluated by the Site Quality Team and Site Production Team to determine the number of media fills that shall be required to re-qualify.

All Aseptic Processing Area (APA) Personnel and APA Support Personnel shall participate in a minimum of one successful media fill per year. New APA Personnel and APA Support Personnel shall be included in the next scheduled media fill and shall not perform critical operations (e.g., operate filling machines, fill stopper bowl) in the Air Classification Grade A area until they have participated in a successful media fill.

Observing is not considered participation.

Environmental and Personnel Monitoring shall be performed during media fills.

Following a Media Fill, the room and equipment shall be cleaned immediately (i.e., start within 4 hours) to prevent contamination of subsequent Filling Operations. Soiled cleaning implements shall be handled in a manner that prevents contamination of filling rooms and equipment.

A Media Fill Failure is declared when acceptance criteria are exceeded. Any contamination shall be investigated. All media fill failures shall be investigated, documented, and a cause for the failure assigned, if possible. The filling line shall not be used for production until remedial action has been taken and the required new media fills are successfully completed.

A Media Fill shall be invalidated when events unrelated to aseptic processing occur that impact the validity of the simulation. Media fills shall be declared invalid when any of the following conditions occur:

*Failure of the Growth Promotion Test;

*Incorrect incubation conditions; or

*Less than the required number of units is filled.

In the case of a culture medium growth promotion test failure, a media fill shall be declared invalid. The filling line can be used for production on a temporary basis, if the cause for the culture medium growth promotion test failure involves: laboratory testing error; media infertility caused by faulty preparation; or media infertility due to an incorrect ratio of sterile placebo material to liquid medium.

Initial Media Fills of each aseptic filling operation shall:

*Consist of a minimum of 3 consecutive, successful media fills;

*Be performed on 3 separate days and/or shifts;

*Be of sufficient duration to simulate all manipulations performed during actual operations; and

*Simulate the aseptic process from the point where the product is considered to be sterile for liquid products and from the point when product is added to the filler for powder filling.

The Media Fill Protocol shall address the following areas:

*Production instructions and Standard Operating Procedures (SOP)intended to be simulated;

*Maximum number of people in the APA, activities, changes, breaks;

*Complexity, aseptic manipulations, speed of filling operations, and Worst Case conditions;

*Maintenance of an event log;

*Duration of media fill;

*Number of units to be filled and incubated;

*Accountability for filled containers and rationale for Rejects;

*Routine and non-routine filling operation interruptions and interventions; and

*Environmental and personnel monitoring.

*The Filling Room shall be cleared and cleaned between each media fill.

For Initial Media Fill Studies, if the filling line utilizes multiple vial types and line speeds, then a container configuration that includes a combination of all worst-case conditions with respect to size, fill, container neck opening, line speed, and manipulations, shall be used.

The justification for these configurations shall be documented for each filling line.

Re-qualification of Each Active Aseptic Filling Operation shall:

*Be performed twice a year at 5 to 7 month intervals on each shift;

*Use a container configuration supported by a justification;

*Consist of a single successful media fill; and

*Be of sufficient duration to perform all manipulations and to simulate actual processing time.

Media Fill Studies shall be performed prior to the next scheduled re-qualification in the case of the following events:

Confirmed sterility test failure where an investigation concludes the need for re-qualification;

When there has been a significant change. Examples of such changes include, but are not limited to:

* Modifications to equipment directly contacting bulk product, drug product, aseptically processed medical device, or containers;

* Modifications to equipment or facilities which can affect air quality or airflow;

* Major changes in production personnel; and

* Initiation of additional routine production shifts; or

* After a shutdown period in which the area has been non-aseptic beyond a Validated time frame, and no changes were made; and/or

Where an investigation concludes that the pattern and/or extent of environmental monitoring excursions appear sufficiently abnormal to suggest the need for re-qualification.

Media Fill Acceptance Criteria shall include (see Fig 1):

*The minimum number of units filled shall be sufficient to allow simulation of all aseptic manipulations, interventions, and other permitted routine activities associated with aseptic filling;

*A minimum of 5000 containers shall be filled and incubated per media fill;

*One contaminated unit shall result in an investigation, including consideration of the need to a repeat media fill based on the conclusions of the investigation; and

*Two contaminated units are considered a media fill failure and are cause for Revalidation, following investigation.

An Investigation of any contaminated units shall include consideration of, and is not limited to, the following:

*Environmental and personnel monitoring data;

*All sterilization process data including Calibration data;

*APA cleaning and sanitization;

*APA and APA Support Personnel training;

*HEPA Filter Integrity;

*Sterilizing Grade Filter Integrity;

*Identification of the microbial contaminant(s);

*Defects identified in media filled units removed prior to incubation;

*Interventions performed at the time the positive unit(s) was filled; and

*Review of any Deviationsor unusual events that occurred during the fill.

When Media Fill Acceptance Criteria are Exceeded the filling line shall not be used for production until 3 consecutive, successful media fill studies have been completed.

The Investigation shall include a review of all Lots/Batches produced on the filling line since the last successful media fill, unless an Assignable Cause is identified with a more recent lot. The rationale for product disposition shall be documented.

Product Filled After a Media Fill shall be placed on Quarantine-HOLD until the Final Reportis approved and any investigations are completed. The rationale for product disposition shall be documented.

Microorganisms found in contaminated units shall be identified to the species level, if possible.

When a Growth Promotion Test Fails, an investigation shall be conducted. The investigation shall result in one of the following conclusions:

Assignable Cause – Laboratory Related: If an assignable cause is identified that is related to laboratory testing (e.g., faulty test technique, incorrect incubation temperature for the samples, non-viable challenge cultures, incorrect culture) then the growth promotion test may be repeated once on the media fill lots/batches. If the Repeat Test results are normal and confirm the presumed assignable cause, then the media fill shall be declared acceptable. If the repeat test fails, the media fill shall be declared invalid; or

Assignable Cause – Related to Medium Infertility: If an assignable cause is identified that is related to an error in culture medium preparation (e.g., overheating, incorrect composition, incorrect gas headspace), or growth inhibition due to an incorrect amount of placebo material in the case of dry powder filling, the media fill shall be declared invalid. Corrective measures shall be identified, implemented, and one successful media fill completed to confirm the presumed assignable cause.

An Event Log shall be maintained by a Qualified person during each media fill to record events (e.g., unplanned interventions) and observations that are not addressed in the media fill protocol. The event logs shall be retained according to current site validation documentation retention policies.

Media fills may also be videotaped. If the media fill is videotaped, the videotape must be reviewed by a qualified person and the results summarized and included in the Final Report. Videotapes shall be retained according to current site validation documentation retention policies.

Microbiological Culture Medium shall:

*Support growth of low numbers (less than 100 cfu per inoculated unit) of microorganisms;

*Be sterilized in the same manner as the production process being simulated, for liquid products;

*Be sterilized using a validated sterilization process for powder products; and

*Be supported by growth promotion tests that demonstrate growth of microorganisms within 5 calendar days.

Media Samples shall be incubated at either of the following conditions:

*For a minimum of 7 calendar days at 20 – 25oC followed by a minimum of 7 calendar days at 30 – 35o C; or

*For a minimum of 14 calendar days at 20-25oC.

An Anaerobic Media Fill must be conducted, when an anaerobic organism is implicated during a laboratory investigation (e.g., anaerobic organisms isolated from a sterility test failure).

Prior to Incubation, media fill containers shall be inverted so that the media contacts the entire inside surface of the container and closure. If possible, media shall be filled in clear containers to allow for visual detection of contaminated units.

Media Fill Containers shall be collected in sequentially numbered trays with the time of collection noted on the tray identification.

Media Fill Containers shall be 100 percent inspected prior to incubation. Units with compromised container/closure integrity that would normally be discarded during production (e.g., cracks, missing stoppers, missing seals after the sealing machine) shall be removed and discarded prior to incubation. The number of units removed and discarded, and the reason for removal shall be documented.

All media filled units that appear integral upon inspection (including those with cosmetic and/or particulate defects, fill weight rejects, and unopened samples) shall be incubated and included in determination of the acceptability of the media fill. A Record shall be maintained of the number and type of each reject.

All Media Fill Containers shall be accounted for and documented, and shall include:

*The total number of units filled;

*The total number (and description) of units rejected prior to incubation;

*The total number of units incubated; and

*The total number of units read at the end of the incubation period.

Media Fill Containers shall be visually inspected for microbial growth by qualified personnel after 14 calendar days of incubation. Media filled in opaque ointment tubes, translucent plastic bottles, or amber containers shall be emptied into separate clear tubes for visual inspection and read immediately after the 14 calendar day incubation.

Positive Growth Promotion Tests shall include the following:

*    Microorganism selection shall be according to applicable Compendia and include at least one environmental isolate;

*    Verification that initial inoculum level is less than 100 cfu;

*    Sample containers shall be collected from the beginning of the filled lot after the initial 14 calendar day incubation period;

*    Sample containers shall be inoculated with the specified growth promotion organism(s) and incubated for 5 calendar days at the temperature range for the organism(s); and

*    Growth in the positive control shall be confirmed as the Indicator Organism(i.e., Gram stain, genus or species identification).

A Batch Record or Device History Record (DHR) shall be completed for each media fill and shall include:

*Documentation normally included in a production filling record (e.g., container/closure sterilization data);

*Documentation of planned/unplanned interventions, including duration of intervention/stoppage, number of trays being filled, and time;

*Data regarding the filled and incubated units, including: # filled; # incubated; # of positive units; # of defective, rejected units for cause; and

* Results of growth promotion tests.

A Final Report on Each Media Fill shall be generated and shall include summary data from the event log, batch record or DHR, and environmental/personnel monitoring. The report shall document a conclusion regarding the acceptability of the media fill and shall be approved by the Validation Committee (VC).

Powder Media Fills shall include:

*Container filled with a sterile, microbiologically inert filling agent (e.g., polyethylene glycol 8000, lactose) to a level that is not inhibitory to microbial growth; and

*Units then filled with sterile liquid media (e.g., Soybean Casein Digest Broth), ensuring inert filling agent is in solution.

Media Fills Simulating Lyophilization shall include:

*A partial vacuum drawn on the lyophilization chamber that is held for a predetermined length of time at ambient temperature, after it is filled with media fill containers having unseated stoppers;

*Release vacuum with sterile air and seat stoppers; and

*Crimp seal vials outside the lyophilizer after stoppers are seated.

In Small Scale Filling Operations (e.g., Clinical Supplies) where a batch size cannot be scaled to fill a minimum of 5000 vials, media fills shall be conducted in triplicate at the maximum scale possible for initial qualification. One media fill shall be performed for re-qualification. The acceptance criteria for each media fill shall be zero contaminated media fill units (see Fig 2).

Powder Media Fills shall include:

*Units filled with sterile liquid media (e.g., Soybean Casein Digest Broth); and

*Container then filled with a sterile, microbiologically inert filling agent (e.g., polyethylene glycol 8000, lactose) to a level that is not inhibitory to microbial growth, ensuring inert filling agent is in solution.

Figure 1: Large scale Media Fill Acceptability Decision Tree

R. Batch and Lot Identification

Each Lot or Batch of Drug Product, Active Pharmaceutical Ingredient (API), Medical Devices, Intermediate, and In-Process Material shall be identified with a Site unique Lot Number or Batch Number from which the complete history of the manufacture, processing, packaging, storage, and distribution of the lot or batch can be determined.

This practice document applies to GMP Production Sites where API, drug products, medical devices, intermediates, and in-process materials are produced for Pharmaceutical, Animal Health, Production Sites and Logistic Centers where Raw Materials (RM) and/or Packaging Materials are received.

Each Supplier Lot of Raw Materials shall be assigned a Site-unique Raw Material Lot Number for each shipment of each supplier lot received.

Each Supplier Lot of Packaging Materials shall be assigned a Site-unique Packaging Material Lot Number for each shipment of each supplier lot received.

A Written Record shall be maintained of the assignment of each batch number or lot number. Reworked Lots or Batches shall be assigned new lot numbers or batch numbers. Assignment and Control of Raw Material Lot Numbers, Packaging Material Lot Numbers, and Batch Numbers or Lot Numbers shall be performed by Qualified individuals in conformance with effective site policies. Every Container of material resulting from or used in Production shall be identified with a unique lot number or batch number for that material. Blending of Multiple Lots (Batches) to make one lot (batch) shall be performed in a manner that ensures blend uniformity, and the new lot (batch) shall receive a new lot (batch) number.

When Different Portions of a Single Lot or Batch are subjected to individual processing such as in terminal Sterilization, Lyophilization or coating, each portion needs to be identified and tested, unless equivalency of the individual processing steps was demonstrated during

Process Validation. Traceability of an individual portion of the single lot has to be maintained until it is determined that the individual portion meets its specified requirements.

Palletized Glass Containers for Sterile Drug Products represent an exception to this Practice, since Labeling each container might jeopardize container cleanliness. An acceptable alternative is to label the shrink wrapping of at least eight modules (“bricks”) on the lowest layer of containers, so that two or more labels are displayed on each face of each pallet.

S. Aseptic Manufacturing Practices

Aseptic Manufacturing Practices shall be established for Aseptic Processing Areas (APA)used in the Production of Sterile Active Pharmaceutical Ingredients (API), sterile Drug Products, and aseptically processed Medical Devices, and shall include, and not be limited to, Standard Operating Procedures (SOP)and/or Specifications Approved by the Site Quality Team and Site Production Team for:

*Design of the facility and equipment;

*Facility and Equipment Qualification;

*Material and personnel flow;

*Contamination control;

*Sterilization of product and non-product items;

*Environmental monitoring;

*Validation of sterilization processes;

*Personnel training;

*Personnel health and hygiene;

*Preventive Maintenance (PM) and change control; and

*Validation of aseptic processing (e.g., Aseptic Processing Simulation).

This practice applies to the GMP sites where aseptic processing operations are performed.

APA Facility Design shall include, and not be limited to:

*   Room and equipment layouts that minimize microbial and particulate contamination of products, including the use of Airlocks;

*   Separate gowning and degowning rooms;

*Establishment of Air Classifications;

*HVAC system(s) that provides Pressure Differentials between rooms of different air classifications and between adjacent rooms of the same air classification; and

*Cleanable continuous, smooth, and non-porous floors, walls, doors, and ceilings free from ledges and with surfaces resistant to repeated application of cleaning agents.

Equipment Used in the APA shall be qualified and include, and not be limited to, the following design features:

*    Smooth product contact surfaces (e.g., 316 L stainless steel) with minimal cracks and crevices, that are easily cleaned, and that are not reactive, additive, or absorptive;

*    Product contact surfaces resistant to rusting, pitting, and corrosion from water, steam, cleaning agents, and sanitizers;

*    Sanitary fittings (i.e., no threaded fittings) for all pipe and hose connections and downward sloping piping with no Dead-Legs; and

*    Mechanical drives and other rotary mechanisms isolated (e.g., external to the APA) to minimize the risk of product or facility contamination.

Material and Personnel Flow shall be regulated to minimize unnecessary activities that increase the potential for introducing contaminants to exposed sterile product and components, or the Aseptic Processing Facility. Design criteria shall include:

*Unidirectional flow of materials and product components to avoid cross flow of clean or sterile materials with dirty materials;

*Staging of Raw Materials (RM)in clean, controlled dispensing areas free of dirt and moisture;

*Access restricted to Qualified, gowned personnel; and

*Material and personnel pass-throughs (i.e., airlocks).

Contamination Control Measures shall be established, validated, and documented and include SOPs assigning responsibility for cleaning and Sanitization. These procedures shall describe the cleaning schedules, methods, equipment, and materials to be used in cleaning.

Sterilization and Depyrogenation Processes for equipment, components, and product (e.g., Filtration, terminal sterilization) shall be established and validated.

Environmental Monitoring Programs shall be established that include routine monitoring for Viable Particulates and Total Airborne Particulates. Procedures shall define monitoring methods, frequency, data collection and review, Alert Levels, Action Levels, and Trending.

Aseptic Processes shall be validated. Aseptic processing of sterile drug products and sterile APIs shall be validated.

APA Personnel and APA Support Personnel shall be trained and qualified prior to being assigned to aseptic processing operations.

Only Gowned APA Personnel and APA Support Personnel shall transfer materials into, and out of, the APA through the airlock.

The Design of the APA Gowning Room shall include:

*Gowning room separated from the washroom by physical barriers (e.g., walls with an outward swinging door into the gowning room designed to be opened without the use of sanitized hands);

*Physical barrier (e.g., bench) in the gowning room, separating Aseptic Gowning Zone from non-aseptic gowning zone; and

*Alarm or interlock system to prevent opening both the gowning room entry door and the door to the APA simultaneously.

APA Gowning Rooms and APA Equipment Pass-throughs shall be designed as airlocks with positive pressure differentials maintained from clean to less clean areas. Airlock doors shall be equipped with visual or audible alarms to signal the opening of more than one door at a time. Positive pressure differentials shall be maintained across wall openings where sterile product exits the APA on conveyors (e.g., airflow from the APA to the packaging area). At a minimum, all wall openings in Grade A and B areas shall be separated from unclassified areas by a Grade C area or a Grade A air supply zone. Capping operations, if located outside of the APA, must be performed within a Grade A air supply zone immediately adjacent to the wall opening where product exits the APA on conveyors.

Washroom Area Features shall include:

*Shoe and hair covers; and

*Disinfectant (e.g., povidone-iodine solution or alcohol foam) for hands and arms.

Gowning Room Features shall include:

*Ready access, from the non-aseptic gowning zone, to sterile gowning articles and sterile disinfectant (e.g., sterile 70 percent alcohol);

*Empty shelf or bench for placing gowning articles while gowning;

*Gowning instructions and diagram or picture of a correctly gowned employee, clearly posted in the aseptic gowning zone. Picture or diagram must be in agreement with applicable current and approved SOP. The applicable SOP and its Effectivedate must appear on the diagram/picture; and

*Full-length mirror in aseptic gowning zone.

For Products Requiring Special Containment Measures, such as live biological agents, 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).

Grade A Environments shall be protected by physical barriers (e.g., flexible plastic curtains, Plexiglas enclosures) to completely or partially (as applicable to the specific application) enclose areas in which aseptic connections and manipulations occur.

Handling of Sterile Products, Raw Materials (RM), and Equipment shall be performed in Grade A environments under Laminar Airflow (LAF)conditions in a manner that does not block or impede LAF, including such manipulations as:

*Aseptic connections and aseptic assembly of manufacturing equipment;

*Opening or closing of sterile processing vessels or Containers;

*Sampling of sterile materials;

*Component additions to sterile vessels;

*Aseptic filling and stoppering of containers;

*Loading and unloading lyophilizers; and

*Sealing of ampoules.

Aseptic Connections and Manipulations shall be avoided whenever possible. If aseptic manipulations are required, only sterile tools (e.g., forceps) shall be used to handle sterile materials. These tools must remain sterile and, as necessary (e.g., when dropped on the floor or upon contact with non-sterile surfaces), be replaced during the operations. Tools shall be placed in sterilized containers between uses.

Aseptic Manufacturing Equipment and Processes used in the manufacture of sterile drug products, sterile APIs, and aseptically processed medical devices shall be qualified and validated using Protocols approved by the Validation Committee (VC):

*Sterile drug product aseptic processing shall be validated using aseptic processing simulation including filling and sealing operation; and

*Sterile API aseptic processing shall be validated by simulating aseptic operations.

Compounding/Storage Vessels that have been sterilized using SIP methods shall be maintained under positive pressure until use. Tanks shall be pressurized with sterile filtered air or nitrogen. Vessels must be drained of steam condensate and dried immediately after sterilization. The sterile hold times of these vessels must be qualified.

Tools Used in the APA (e.g., wrenches, screw drivers, forceps) shall be cleaned and sterilized prior to use. Instrumentation (e.g., Calibration standards) shall be cleaned and sterilized prior to use in the APA. Where sterilization is not possible, sanitization measures shall be used during entry into the APA through an airlock.

Materials shall be transferred into the APA through the APA airlock following a validated, sanitization process, for example:

a)    Materials are moved into the non-aseptic side of the APA airlock using a non-aseptic area transfer cart or skid;

b)    The materials on the non-aseptic area transfer cart are sanitized for a validated contact period;

c)    Gowned APA Personnel or APA Support Personnel enter the airlock from the APA and transfer materials to an APA dedicated cart in the airlock;

d)    APA Personnel or APA Support Personnel sanitize the materials and leave for a validated contact period on the cart or skid; and

e)    APA Personnel or APA Support Personnel move the materials on the APA dedicated cart into the APA.

Sterile Containers used to hold tools while working in the APA shall be replaced, at least, once per shift, or sooner, if contamination is suspected (e.g., from frequent handling). If contamination is suspected, sterile containers used to hold tools while working in the APA shall be replaced immediately.

Glass Vials used to package sterile drug products shall be provided from the Supplier in plastic shrink-wrap packaging.

Items Purchased Sterile (e.g., plastic ophthalmic bottles, tubes, product ingredients) shall, at a minimum, be double bagged by the supplier, if a validated sanitization process is followed on the outer bag when transferring the materials into the APA via an airlock; otherwise such materials shall be tripled bagged. When transferring bagged material into the APA via an airlock, the material shall be removed from the bags according to SOPs.

SOPs describing equipment and/or line clearances in the event of unplanned interventions, such as machine adjustments, repairs, and power outages, shall be established. Any unplanned intervention or process stoppage while an aseptic process is running shall be:

*Accomplished with sterile tools or equipment using Aseptic Techniques;

*Investigated; and

*Documented in Batch/Lot records.

When Equipment Maintenance has been performed in the APA, the area and equipment shall be cleaned, disinfected, and/or sterilized before processing resumes. Maintenance activities, cleaning, disinfection, and sterilization shall be documented in the batch/lot records.

The Maximum Length of Time clean, sterile equipment or components may be held prior to use shall be determined and validated. Sterile equipment or components held beyond validated time limits shall be removed from the APA.

Materials That Contribute to Foreign Matter, including and not limited to the following, shall be prohibited from the APA:

*Aluminum foil;

*Cardboard;

*Wood (e.g., wooden pallets); and

*Office paper and paper wrappings on sterile gowns, boots, and gloves.

Non-Particle Shedding, Sterilized Clean room Paper and Pens shall be used in the APA when needed to record activities or data. Standard office paper and supplies shall not be used in the APA.

Sources of Stagnant Water or Other Stagnant Liquid (e.g., puddles on the floor from facility cleaning or equipment/utility leaks) shall be eliminated immediately upon detection.

Equipment shall be dried immediately after sterilization.

The Number of Personnel within the APA shall be limited by SOPs to the minimum number required for the task and the maximum number supported by validation

(e.g., aseptic processing simulation).

Personnel shall adhere to established APA practices including, and not limited to:

*Do not reach or lean across open product hoppers, or exposed sterile product, raw materials (RM), or equipment;

*Do not pick anything up from the floor or contact the floor with a gloved hand. If gloves contact the floor, reglove according to outer glove instructions;

*Avoid contact of gloves and gown with walls;

*Avoid touching any part of the gown;

*Do not block air returns with your body or equipment;

*Transport material at waist height;

*Avoid excess talking;

*Sanitize gloved hands frequently (e.g., every 5-10 minutes) using a sterile disinfectant (e.g. 70 percent alcohol);

*Perform slow and deliberate movements;

*Limit entries and exits of people and objects in Grade A areas;

*Limit entries and exits of people within the APA;

*Avoid direct contact with sterile surfaces; and

*Avoid obstructing the path of LAF.

Visiting Personnel(e.g., building or maintenance contractors) planning to enter the APA shall be:

*Instructed in aseptic gowning;

*Gowned under the direct supervision of qualified APA personnel;

*Accompanied by a qualified APA colleague at all times; and

*Tested for viable particulates upon exit from the APA.

Personnel Involved in Processing Animal Tissue or Microbiological Cultures shall not enter the APA unless a decontamination process, including changing clothing, is followed.

Qualification and Planned Maintenance shall be performed on equipment supporting the aseptic operation, including and not limited to:

*Sterilizers,

*Stopper processing equipment,

*Air handling and Filtration Systems,

*Gas and Vent Filters,

*Water storage and distribution systems,

*Clean Steamsystems,

*Depyrogenation ovens/tunnels, and

*Compressed gas systems.

Change Control and Revalidation Measures shall be implemented to identify, document, and review changes (e.g., to facilities, procedures, equipment, cleaning, and sterilization) that impact the validated state of aseptic operations.