Guidance Summary 101 - 110
Guidance 101 Summary - Clean Steam Systems
This document provides guidance for clean steam used in aseptic applications, and applications where the steam or condensate directly contacts products or materials, or direct product contact surfaces (i.e., equipment, containers, closures).
- Quality Monitoring of the Feedwater should be performed according to established procedures and schedules.
- Clean Steam Sampling Procedures should be established and sampling personnel should be qualified in these procedures.
- When Operating Continuously, the Clean Steam Generator and Distribution System should be sampled and tested against specifications as follows:
- Weekly sampling of the generator;
- Monthly sampling from at least one Critical Use Point (CUP) located outside the Aseptic Processing Area (APA); and
- Use points sampled on a rotating basis so that all use points are sampled, at least once, every six (6) months.
Following any shut down, samples from the generator and all use points should be taken and tested before use is authorized to resume.
4. Clean Steam Condensate Samples when required for Bacterial Endotoxin Testing (BET) should be collected in endotoxin free containers using a technique designed to minimize microbial contamination of the samples. BET should be conducted as soon as possible after collection. The time of collection should be recorded.
Guidance 102 Summary - Cleaning and Sterilization of Aseptic Manufacturing Equipment
This document provides guidance in the cleaning and sterilization of aseptic manufacturing equipment to minimize the risk of particulate and microbiological contamination.
1. Washing Bays for Initial Cleaning and Final Rinsing of Equipment should include, and not be limited to, the following design considerations:
- Floors sloped to a drain;
- A minimum two (2) inch (5cm) air break to drains;
- Water contained and drained within the washing bay;
- Ventilated area to minimize condensation on ceilings and walls; and
- Utilities identified (e.g., water, filtered compressed air).
2. Equipment Washing Machines or Cabinets used to clean small pieces of equipment (e.g., beakers, clamps) should include, and not be limited to, the following design considerations:
- Stainless steel construction, designed to drain and not retain water;
- Effluent water sample port;
- Stainless steel trays and/or baskets designed to be self-draining; and
- Mechanism to remove excess moisture after washing.
3. Equipment should be cleaned promptly after use. The maximum time interval for leaving equipment in the soiled state should be specified and should not exceed fourteen (14) calendar days.
Guidance 103 Summary - Container Closure Integrity for Sterile Drug Products
Critical Factors That Affect Container Closure Integrity should be defined in written Standard Operating Procedures (SOP), controlled, and monitored and including, and not be limited to:
- Package component composition, dimensions, coatings, and critical defects;
- Sealing/packaging operation variables of time, temperature, pressure (seal force), gas flow rates, and torque;
- Processing variables of packaging components including washing, drying, siliconization, depyrogenation, and sterilization; and
- Final product processing, such as terminal sterilization or lyophilization.
Challenged Containers that Show Microbial Growth Upon Microbial Ingress Testing should be inspected to determine whether defects in the container closure seal permitted microbial ingress. All defects observed should be described and documented. An investigation should be conducted to determine the cause of the contamination, including a comparison of the contaminant organism(s) to the challenge organism.
Non-Microbial Methods for Container Closure Integrity Testing should be based on validated studies that correlate the test method to microbial ingress testing. Non-microbial integrity tests should be used during routine processing, at a minimum:
- During equipment set-up;
- As an In-Process Control (IPC) test;
- On representative samples of the finished batch/lot; and
- On stability samples during the shelf life and at lot expiration date.
Guidance 104 Summary - Controlling the Microbiological Quality of Solid Oral Dosage Forms
To control the microbial quality of a non-sterile Solid Oral Dosage (SOD) form, it is potential sources of microbial contamination. The microbial quality of a solid oral dosage form can be managed by identifying and controlling the microbial contamination sources relevant to the non-sterile manufacturing process. A microbial hazard is defined as any circumstance in the process that allows a microbial contamination event to occur.
After the microbial hazards are identified, the existing measures in the process, if any, are evaluated to determine if they are effectively controlling the identified microbial hazards.
There are specific circumstances or situations within the manufacturing process that may allow for a microbial hazard to occur. An assessment of the manufacturing process would include a review of the following:
- Manufacturing equipment
- Cleaning & sanitization methods
- Water / utilities
- Processing conditions
- Pre/post manufacturing storage & transport conditions
Microbial hazards may be introduced into a manufacturing process due to the improper Inadequate equipment maintenance may also serve as a potential microbial hazard. Microbial hazards may also originate from improper facility design. microbial hazards could include the following:
- Cleaned equipment that is not properly dried after cleaning and stored water wet.
- Cleaned equipment that is not properly stored.
Microbial hazards can arise if key processing conditions employed during the manufacturing of an SOD are not properly established or controlled. Microbial proliferation could readily occur. Inappropriately maintained and controlled warehouse and storage areas maybe potential microbial hazards.
A risk assessment of the non-sterile manufacturing process is a recommended means to determining potential microbial hazards.
Guidance 105 Summary - Defining Worst Case Conditions for Aseptic Process Simulations
What are the “worst case” attributes to be considered in an aseptic process simulation (i.e. media fill program) for aseptic filling of sterile drug products within conventional cleanrooms?
Aseptic process simulation tests (e.g. media fills) “are used extensively and are recognized as an effective way to validate aseptic filling” processes for the purpose of complying with regulatory GMP expectations. A media fill begins at the point where the final sterilization of the product takes place (i.e. where aseptic operations are performed) through the completion of filling operations with the sealing of the filled containers.
Media fill operations involve aseptic filling using microbiological growth medium in place of the product. This document presents the common “worst case” attributes to be considered within a media fill program for aseptic manufacturing processes. Also, “worst-case” conditions should be considered and defined within the media fill simulation program for product holding times, process filling times, filling line speed, container sizes, interventions and personnel.
Media fill process design should also consider not only specific product filling line equipment and components, but also local facility (e.g. HVAC) and environmental characteristics (e.g. personnel traffic patterns, process flow, etc.) where the aseptic filling operations take place.
Other media fill design options can be used and may include performing the media fill immediately following the completion of routine production operations, which is also known as “piggybacking”, or alternating the filling of media fill vials with just operating the filling equipment (without vial filling) to allow for continuous processing time while minimizing the total number of media filled vials.
The media fill program design should consider and is expected to “emulate the regular product fill situation in terms of equipment, processes, personnel involved and time taken for filling as well as for holding”. As part of media fill design, there is an expectation to consider “worst case” conditions. A number of these have been presented including: holding times, aseptic process times, number of units, line speed, container size, process matrix, personnel, process setup, and interventions. Within each of these highlighted categories an attempt has been made to provide guidance on what to consider a “worst-case” condition within the media fill program.
Guidance 106 Summary - Explanation of Repeat Testing & Retesting During Micro OOS Investigation
Microbiological repeat testing may be defined as additional laboratory testing performed to replace original invalid data when a laboratory assignable cause has been identified.
The repeat test result is intended to replace the original invalidated OOS test result. Microbiological repeat testing is very similar to repeat testing conducted during analytical laboratory investigations. If an assignable cause is clearly identified, the initial OOS test result is invalidated and the original testing is repeated to generate a valid result.
Unlike microbiological testing, some analytical test methods consist of multiple analyses per test sample.
Retesting may be performed only to corroborate or confirm the original OOS test result. If the retest results do confirm the initial OOS test result, this data can be used to support the case that the initial OOS test result is valid and not due to laboratory contamination. A confirmed OOS test result will cause the rejection of the test article (unless approved for reprocessing).
Retest results alone cannot be used to invalidate the initial OOS test result. Only a clearly identified assignable cause can invalidate the initial OOS test result.
Microbiological retesting is significantly different to the retesting conducted during analytical method laboratory investigations.
Analytical laboratory investigation retest results can be utilized to overcome the initial OOS test result after evaluation by Q.A. management. Microbiological retest results are only used to corroborate or confirm the initial OOS test result.
Microbiological OOS retesting differs significantly from analytical method OOS retesting with regards to testing requirements and data interpretation.
Guidance 107 Summary - Gamma Radiation Sterilization
Critical Process Parameters for gamma radiation sterilization include:
- Exposure time,
- Timer setting (batch mode processing),
- Conveyor speed (continuous mode processing),
- Dose measurement.
Gamma Radiation Commissioning and/or Qualification should include, and not be limited to, documentation of the following:
- Verification that the gamma irradiator is installed according to design criteria;
- Identification of irradiator location within the facility and flow of materials through the facility;
- Description of the construction and operation of the irradiator, including the conveyor system and timer;
- Description of the irradiation carriers, including materials of construction and dimensions;
- Identification of I/Es used to control, monitor, and record critical process parameters;
Establishment of a Sterilization Dose Using AAMI Method 1 for a Single Production Batch includes the following steps:
- Determine the average indigenous bioburden of the API, drug product, medical device, or non-product item using ten (10) randomly collected samples;
- Determine the verification dose for a Sterility Assurance Level (SAL) of 10-2 from an AAMI table using the average bioburden
- Verify that the verification dose does not exceed the established maximum sterilization dose limit;
Guidance 108 Summary - Lyophilization
Collapse Temperature – in the lyophilization of amorphous systems, that temperature below which primary drying must occur to prevent loss of product cake structure (i.e. melt back).
Degree of Super cooling – the number of degrees below the equilibrium freezing temperature where ice first starts to form.
Eutectic Temperature – for crystalline solutes, a point of a phase diagram where all phases are present and temperature and composition of the liquid phase cannot be altered without one of the phases disappearing. Primary drying must occur below this temperature to allow for complete sublimation.
Commissioning and Qualification of Lyophilizers should include the following:
- Vacuum leak rate, maximum vacuum level, chamber pressure control, and condenser capacity are verified;
- A minimum of three temperature distribution studies on an empty chamber are conducted to confirm shelf temperature control and uniformity at three temperature ranges representing the three phases of the lyophilization cycle (i.e., freezing, primary drying, and secondary drying);
- At least one product study is conducted using simulated or actual product; and
- Media Fills are performed.
Guidance 109 Summary - Lyophilizer Loading and Unloading Recommendations
This article addresses questions raised by lyophilization (freeze drying) facilities involving in using of automated loading and unloading systems for new lyophilizer installations. Further, with separate carts dedicated to loading and unloading, different products can be simultaneously loaded and unloaded in the same transfer corridor.
A single cart should not be used to load and unload different products without cleaning between these uses. The options described below address conditions using single and multiple transfer carts and situations with multiple lots of the same product as well as operations involving different products utilizing freeze dryers which involve loading and unloading from the same side.
The FDA set similar requirements in their earlier Guide for Inspection of Lyophilization of Parenterals. Here, they state “The transfer and handling, such as loading of the lyophilizer, should take place under primary barriers, such as the laminar flow hoods under which the vials were filled. Validation of this handling should also include the use of media fills.”
It can be recommended that transferring to (the) lyophilizer and loading into and unloading from the lyophilizer shall be processed using aseptic technique in a Grade A environment with a Grade B background. The stoppered vials shall remain in a Grade B environment and shall be conveyed to the stopper/sealer under Grade B conditions.
A potential source of cross contamination can arise from dried product which is exposed during unloading. Such product can come in small amounts from splashes and breakage during filling and loading and vapour deposition and vial breakage during lyophilization. HEPA filtration in the room and on the cart(s) should be designed to prevent the transfer of dried product. Smoke testing should be used to demonstrate air exhausted from one cart is not transferred to another.
Guidance 110 Summary - Microbial Attributes Testing of Non-Sterile Solid Oral Dosage Form
The intention of this document is to provide guidance to determine the need for performing microbial attributes testing of drug product raw materials, non-sterile excipients, active pharmaceutical ingredients (APIs), and finished drug products. This guidance is recommended in order to ensure the microbiological quality of any non-sterile solid oral dosage form.
It is not mandatory to examine the microbial quality of drug product raw materials, non-sterile excipients, APIs, and finished solid oral drug products unless required by the compendia or a regulatory filing. However, a microbial assessment should be performed on all raw materials, non-sterile excipients, APIs, and finished drug products that are not required to be tested by compendia or regulatory filing.1 This assessment will determine if microbial attributes testing is warranted.
Microbial attribute testing estimates the number of and/or types of microorganisms present in a sample of material or product by utilizing the total aerobic bacterial count test, the total yeast and mold count test, or the presence of specified microorganisms test. Because of the wide diversity of materials and finished solid oral drug products, not all products are equally susceptible to microbial contamination, and therefore, microbial attributes testing may not be the same for all products. This guidance has been developed to help determine the need for microbiological testing.
Recommendations
Materials:
The raw materials, non-sterile excipients, and APIs of a solid oral dosage form are considered a potential major source of microbiological contamination in pharmaceutical products. Consequently, a risk assessment of each material is recommended to determine if microbial testing is appropriate. In order to assess each material used in the manufacture of non-sterile solid oral dosage forms, a decision tree has been appended to this guidance (see figure 1).
This decision tree is based upon such factors as regulatory requirements, material source, water activity5, inherent inhibitory or antimicrobial properties, nutrients available for growth, historical bioburden data, and the manufacturing process of the material. A rationale for the decision to test or not to test can be generated based upon this decision tree. If it has been determined that testing of a raw material is needed, microbial attributes testing performed by the supplier can be accepted in lieu of on-site testing, provided that shipping and storage conditions are properly controlled and that the supplier has been audited and approved by a qualified site audit.