by Jeanne Moldenhauer
The burden is placed on global pharmaceutical companies to develop procedures that comply with confusing requirements.
International harmonization of standards has been ongoing for several years notably in the area of compendial tests and monographs. However, steam sterilization regulations and standards, especially as they affect cycle development and validation, lack consistency and uniformity among the various international regulatory bodies. Very little has been done to reconcile these differences.
Many pharmaceutical manufacturers conduct global businesses, and global requirements for sterilization are a constant source of frustration. There does not appear to be any effort to standardize sterilization requirements by the international harmonization groups (groups from different countries that belong to a committee that is trying to make one set of requirements that applies to all member countries). This forces companies to make tough business decisions when it comes to product terminal sterilization, such as establishing overly stringent sterilization cycles so that they can meet all regulations and standards where product is sold. Alternatively, sales may be limited to markets with similar standards, or attempts may be made to maintain complex systems of product specifications for each market to ensure compliance with a variety of global standards. These practices increase the costs of drug product manufacturing.
In the December 3, 1993, Federal Register, FDA issued proposed guidelines for the sterilization process validation documentation to be included in product applications. The guidance was made official in November, 1994. Although the FDA document is labeled “guidance,” it is viewed for compliance by the Agency when abbreviated new drug applications (ANDAs), generic drugs, are reviewed for approval. So essentially, it is being used as a regulation. Around the same time in 1994, the United Kingdom Medicines Control Agency (MCA), the UK equivalent of FDA, published a document relating to sterilization and sterilization validation (HTM 2010), which introduced a new set of controversial requirements for sterilizer qualification and for testing steam quality. Europe also has the EU GMP Guide Sterile Annex I, Manufacture of Sterile Medicinal Products. Additionally, there are numerous ISO (11134:1994, 11138-1:1994, 11138-3:1995, 11140-1:1995, 11140-2:1998. 13863:1997) and EMEA (Proposed Decision Tree) documents in various stages of approval on the topic of steam sterilization. Finally, the Pharmacopoeias of several nations and the European Union also offer conflicting information on sterilization and/or the use of biological indicators.
With this undue emphasis on independent steam sterilization regulations around the world, an enormous burden has been placed on global pharmaceutical companies to develop processes and procedures that comply with all the different and sometimes confusing requirements. The ideal situation would be to have one set of sterilization standards that is universally accepted, and is based on sound scientific principles and the achievement of an agreed upon sterility assurance level. Many of the existing regulatory documents contain other approaches that are outmoded beliefs, which have little or no foundation in sterilization science. Agalloco, Akers and Madsen (1998) published an article in which they summarized and explained the various myths associated with steam sterilization. Individual companies find it even more difficult and frustrating to deal with interpretations of steam sterilization guidelines by regulatory agents during facility inspections when convention, not science, is the basis for the regulations that are being enforced.
With this current industry situation in mind, the Parenteral Drug Association formed a task force in 1998 consisting of U.S. and European members whose goal is to rewrite Technical Monograph I: Steam Sterilization. At the time of its inception, the task force set an agenda to expand the old document, make it more user friendly, include more easily understood sterilization scientific theory, and help debunk the myths that have found their way into the numerous regulatory documents. The most recent draft of the revised FDA monograph (Revision 8) is available for review and comment on the PDA Web site (www.pda.org). The task force welcomes all comments and suggestions. Since the initial formation of the PDA steam sterilization task force, there have been several international conferences initiated by PDA and International Institute for Research (IIR) to address myths and realities related to steam sterilization and its associated subset, Parametric Release.
One of the most difficult problems in reconciling the various international requirements for steam sterilization into one document, is that the existing documents do not “speak the same language.” Sterilization models or approaches are based on overkill cycles, combination bioburden/biological indicator based cycles, or absolute bioburden based cycles. European regulations published in the European Pharmacopoeia and EMEA documents define an overkill cycle as exposure to 121 degrees C for 15 minutes, with timing to begin after all parts of the load have reached set point temperature. The U.S. Pharmacopoeia, on the other hand, defines an overkill cycle as a 12 log cycle reduction of organisms with a D121°C value of at least one minute (e.g., F0 = 12 minutes). Neither one of these “overkill” cycle definitions addresses a standard Sterility Assurance Level (SAL), so one cycle cannot be equated with the other. When a definition for the relatively simple concept of “overkill” cannot be agreed upon, it makes it virtually impossible to understand and communicate more difficult ideas such as F0 or SAL approaches to sterilization cycle development and validation.
The accompanying tables show some of the more familiar international documents dealing with steam sterilization and list the information contained in them. In some cases, current issues or concerns are also mentioned. The documents cited do not cover all the standards and regulations that exist at this time, but they do illustrate many of the difficulties facing drug manufacturers.
As a global pharmaceutical community, we want to initiate actions. Discussing what is wrong with a system unfortunately, does not provide the leadership to make change happen. Those individuals who have to use these regulations/standards understand that this is confusing and conflicting. Politicians and diplomats have no interest in taking the lead in resolving this conflict.
Currently, there is no mechanism in place which clarifies or promotes the harmonization of sterilization standards and regulations, other than the international effort behind the revision of the PDA Monograph No. 1. Until action steps are taken, this area will probably be a headache for many years.
Health Technical Memorandum (HTM) 2010 Part 3: Validation and Verification
Validation of sterilizers cannot be retrospectively validated by product inspection or testing. Testing of a sterilizer occurs at several stages including: after delivery, during validation, periodic evaluations, and following modifications. Maintenance (preventative and corrective) is important, as well.
The following European Standards are applicable to this document:
· EN550 (Ethylene Oxide Sterilization)
· EN554 (Moist Heat Sterilization)
· EN556 (Requirements for Medical Devices to be labeled “sterile”)
· BS4196 (Sound pressure test)
· EN866 (Biological Indicators)
This document covers the validation and periodic testing of the various sterilization processes used in hospitals, laboratories and other healthcare facilities.
This document covers all types of sterilization processes.
1. The document (G2.7-2.35) specifies validation tasks to be performed by the purchaser, manufacturer and the contractor. Since many manufacturers/contractors are not regulated themselves, some of this document may be hard to enforce. There should be some allowances for the regulated user to negotiate/decide who performs what tests.
2. Many of the required installation tests are specified and provide a useful checklist of testing to be performed. Other tests have specified methods to perform the test which may not be the most efficient or practical test method (i.e., the test method is very old).
3. Some tests specified may provide useful information for hospital sterilizers, however, the parameters being considered are not issues for pharmaceutical grade sterilizers (i.e., the design has been improved to resolve these issues by the sterilizer design).
4. The requirements for laboratory sterilizers provide exposure times and temperatures without consideration for the sizes or volumes of the liquid filled containers. It also does not take into account that the liquid media should be useable after the cycle.
5. The technical and scientific aspects of the steam quality tests are challenged by many sterilization experts.
6. The document includes specified times for many safety and maintenance checks, which are outside the scope of most other regulatory documents.
7. Biological indicators are not normally required for validation (G7.50). Unfortunately, thermocouples do not assess steam penetration to the product. The biological indicator lethality assesses the total effect of the sterilization process on the microbial load.
8. Covered in this document are:
· Testing of sterilizers
· Schedule of installation checks
· Schedule of validation tests
· Schedule of periodic tests
· Test equipment
· Testing methods
· Performance qualification
· Steam quality tests
· Sound pressure tests
· Chamber integrity tests
· Automatic control test
· Porous load sterilizers
· Fluid sterilizers
· Sterilizers for unwrapped instruments and utensils
· Dry heat sterilizers
· LTS disinfectors and LTSF sterilizers
· Ethylene oxide sterilizers
· Laboratory sterilizers
· Extensive glossary
Sterilization Process Validation in Human and Veterinary Drug Products
Effective November, 1994
This document is designed to provide guidance to industry on the sterilization process validation documentation to be submitted in sterile drug applications for humans and animals.
NOTE: It does not affect the Federal Register of October 11, 1991 (56 FR 51354) regarding use of Aseptic Processing and Terminal Sterilization. FDA wants the data submitted to ensure that the processes and methods described do, in fact, obtain the purported results.
This document covers Terminal Moist Heat Sterilization, Aseptic Filling, and other sterilization processes (e.g., Radiation, Ethylene Oxide).
1. Although the document is labeled guidance, it has become a de facto regulation since it is used literally by reviewers to determine whether or not a drug application should be approved.
2. This document includes the following topics (Steam sterilization area contents, only).
·Description of the process and product
– Drug product and the container-closure system
– The sterilization process
– Sterilizer process and performance specifications
– Sterilizer loading patterns
– Methods and controls to monitor production cycles- Requalification of production sterilizers
·Thermal qualification of the cycle
– Heat distribution and penetration studies
– Thermal monitors
– Effect of loading on thermal input
– Information included in the batch record
· Microbiological efficacy of the cycle
– Identification and characterization of bioburden organisms
– Specifications for bioburden
– Identification, resistance, and stability of biological indicator
– Resistance of the biological indicator relative to that of bioburden
– Microbiological challenge studies
· Microbiological monitoring of the environment
· Container closure and package integrity
– Simulation of the stresses of processing
– Demonstrate integrity following the maximum exposure
– Multiple barriers
– Sensitivity of the test
– Integrity over the product life
· Bacterial endotoxins test and method
· Sterility testing methods and release criteria
· Evidence of formal, written procedures
EMEA Decision Tree for the Selection of the Sterilization Methods
Effective August, 1999
Sterile products should be terminally sterilized in their final product container (assumes a standard cycle). If this is not possible, the decision tree provides a method to determine which sterilization process should be used.
Going down the paths of the decision tree reduces the level of sterility assurance of the product and this relates to the allowable levels of pre-sterilization bioburden.
* Commercial considerations are precluded as a justification for not using terminal sterilization with the highest level of sterility assurance.
* Heat-labile packaging material alone cannot be the sole reason for adoption of aseptic processing.
Flow charts are provided for aqueous formulations, as well as, non-aqueous liquid or powder products.
1. For aqueous solutions, the primary cycle to be used is 121 degrees C for 15 minutes. This cycle does not take into account the effect the solution has on the biological indicator used. It is common for Potassium Chloride solutions to raise the D-value of the biological indicator to 4 or 5 minutes. If the primary cycle had a true F0 of 15 minutes, it would only be a 3 or 4 log reduction of the biological indicator. PDA comments on the proposed document requested a change based upon Sterility Assurance Level (SAL) achieved.
2. The second cycle selection allows use of an F0 = 8, if the SAL is at least 10-6. Unfortunately, the first cycle does not require an SAL of at least 10-6.
3. The decision tree provides no guidance on environmental monitoring associated with these cycles.
4. For non-aqueous liquids or powders, dry heat sterilization is the first choice for sterilization.
AAMI/ANSI S725-1987 Guideline for Industrial Moist Heat Sterilization of Medical Products
The guideline is intended to provide a description of the essential elements of Good Manufacturing Practices for steam sterilization.
The document covers cycle development, validation, and control of industrial moist heat sterilization.
1. This document was prepared by a group of personnel representing numerous companies and disciplines.
2. The document is not widely recognized by industry or regulatory bodies.
3. Separate standards apply to non-industrial applications.
4. The contents of this document are:
· Applicable documents
· Product and package considerations
– Product considerations
– Packaging considerations
– Shelf life
– Product labeling
– Sterilizer construction, utilities, components, accessories and controls
– Sterilizer cycles (by process type)
– Performance of systems
– Alarm systems
· Sterilization process development
– General principles
– Cycle development for solutions, microbial methods, closures, devices and components, processing equipment and supplies, physical parameters, and F0 value.
· Sterilization process validation
– Engineering validation requirements
– Installation qualification requirements
– Operational qualification requirements
– Performance qualification with product
· Manufacturing (routine moist heat sterilization)
– Steam sterilization process controls
– Microbiological testing
– Release of sterilized products
– Maintenance of validation
– Operational practices
· Reference documents
· Steam tables
Acknowledgements: The following individuals provided invaluable help in the preparation of this article: Goran Bringert, Kaye Instruments; Richard Wood, Ph.D., Pfizer; Timothy Lord, Eli Lilly & Co.; Russell Madsen, PDA; Jim Lyda, PDA; Thomas Berger, Ph.D., Abbott Laboratories; Carol Zaccari, Jordan Pharmaceuticals, Inc.; Elizabeth Joyce, Jordan Pharmaceuticals, Inc.
Jeanne Moldenhauer, Ph.D., is vice-president of Regulatory Affairs and Pharmaceutical Services at Jordan Pharmaceuticals, Inc. Previously, she worked at Fujisawa USA Inc. and Baxter. She has spent over 25 years in the area of sterile process validation and sterility assurance.
- Agalloco, James; Akers, James; Russell E. Madsen, “Moist Heat Sterilization – Myths and Realities”, Journal of Parenteral Science and Technology, 52(6), 11/98.
- Health Technical Memorandum (HTM) 2010 Part 3: Validation and Verification, Copyright 1994
- European Agency for the Evaluation of Medicinal Products (EMEA) Decision Tree for the Selection of the Sterilization Methods Effective August, 1999
- FDA Guidelines for Industry for the Submission of Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products Effective November, 1994
- AAMI/ANSI S725-1987 Guideline for Industrial Moist Heat Sterilization of Medical Products, Copyright 1987
- Monograph #1: Steam Sterilization rewrite draft, available in draft documents at http://www.pda.org.