1. Purpose
The purpose of this Guideline is to provide guidance for the microbiological testing of non-sterile products. This guideline should aid in assuring that the products manufactured at each of the company sites as well as by a contract manufacturer should meet the appropriate regulatory and company requirements and that there is a standardized, company-wide approach to the basic concept of microbiological quality control of non-sterile products. The purpose of this guideline is also to outline the requirements for the analysis of non-sterile drug products as per the harmonized pharmacopoeia (Ph Eur, General Text 5.1.4; USP, General Information Chapter <1111>; JP, Chapter to be determined) General Text/Chapters on the microbiological quality of non-sterile pharmaceutical preparations. Herbal medicinal products are outside the scope of this guideline.
Note: These General Text/Chapters are published for information and guidance only; they are not a mandatory part of the pharmacopoeia.
2. Scope and Applicability
This guideline applies specifically to microbiological testing of non-sterile products, as it can be carried out at any site worldwide, as well as at third party testing labs. In addition to the guideline, the following items should also be in place:
Standard Operating Procedures (SOPs)
SOPs should be developed by the appropriate operational units to provide clear direction for the execution of the testing procedures, material preparation, data analysis, and the development of the documentation referred to in this guideline.
Validation Protocols
Validation protocols should be generated by the appropriate operational units to verify and document that the methods and equipment used to perform microbiological testing can reliably and consistently detect micro-organisms that may be present in units being tested. These protocols, the data generated, and the associated validation reports should provide documentation of the acceptability of these methods and equipment for their intended use.
3. Definitions
3.1 Ph Eur
Ph Eur is the European Pharmacopoeia.
3.2 USP
USP is the United States Pharmocopeia.
3.3 JP
JP is the Japanese Pharmocopeia.
4. Responsibilities
4.1 It is the responsibility of the appropriate operations management to establish, and ensure compliance with this International Guideline for microbiological testing of non-sterile products.
4.2 It is the responsibility of each operation unit using third party testing labs to ensure that this International Guideline is adhered to.
4.3 It is the responsibility of R&D management to initiate a formal microbiological risk assessment at the appropriate time in development and for it to be completed during Phase III. It is the responsibility of each receiving site to review the R&D risk assessment and produce their own risk assessment based on their manufacturing process and plant. It is the responsibility of Operation sites to control changes that could impact the outcome of the microbiological risk assessment during the product lifecycle.
5. Guideline
5.1 Microbiological Testing
5.1.1 General Requirements These items should be addressed in approved methods &/ procedures:
5.1.1.1 Microbiological testing must be carried out in a suitable clean environment that meets the appropriate regulatory requirements.
5.1.1.2 An appropriate sanitization program for the microbiological test area and the associated methods and procedures must be in place.
5.1.1.3 Appropriate preventative maintenance procedures and programs for critical equipment and systems must be approved and in place.
5.1.1.4 Critical instruments and equipment must be calibrated and included in the routine calibration program. Monitoring of critical equipment may be required as appropriate.
5.1.1.5 Sterilization cycles for internally processed media, equipment and materials must be validated.
5.1.1.6 Analysts or technicians must have appropriate training and documentation of that training should be on file and available for review.
5.1.1.7 Validated test methods and or procedures must be approved, current and available for use by the analysts or technicians.
5.1.1.8 Compendial test methods must demonstrate that they are suitable for their intended use.
5.1.1.9 Non-compendial test methods must be validated and demonstrate that they are appropriate for their intended use.
5.1.1.10 Samples must be taken in accordance with approved sampling procedures.
5.1.1.11 All materials, controls and systems sourced externally must be covered by a suitable vendor assurance program.
5.1.2 Methods and Procedures The following additional items or issues should also be addressed in approved methods and/or procedures:
5.1.2.1 Sample Collection, Transport and Storage.
5.1.2.2 Positive and Negative Controls (Growth Promotion) of media for cultivation.
5.1.2.3 Incubation of Test Samples.
5.1.2.4 Preparation, Testing, Approval and Storage of Test Media Reagents.
5.1.2.5 Policy on identification of organisms.
5.1.2.6 Gowning.
5.1.2.7 Out of Specification (OOS) Result Investigation and Response.
5.1.2.8 Test Failure Investigation and Response.
5.1.2.9 Decontamination and Disposal of Testing Waste.
5.1.2.10 Interpretation of Test Results.
5.1.2.11 Retesting. 5.1.2.12 Trending of Test Data.
5.1.2.13 Change Control.
5.1.2.14 Labeling media.
5.1.2.15 Recording, storing and archiving data.
5.1.3 Validation
5.1.3.1 Test methods and procedures, and equipment must be validated to assure the reliability of the data generated by the testing program.
5.1.3.2 All proposed changes to validated systems, processes, equipment or methods must be reviewed for regulatory impact and approved by appropriate management prior to the change. Any changes that impact the status of a validated system process, equipment or methods may require revalidation of that system, process, equipment or method.
5.2 Microbiological Testing, According to the Harmonized Pharmacopoeia
5.2.1 Testing Frequency
5.2.1.1 Non aqueous preparations for oral use:
A risk assessment should be performed to determine the appropriate testing frequency based on the level of risk to the microbiological quality of the product. If the risk assessment demonstrates sufficiently low risk, no testing may be required. The risk assessment, with justification for the proposed testing frequency, must be documented and kept on file. When testing is performed, excursions from compendial standards should be fully investigated and remedial action, including, where appropriate, revalidation and testing on a more frequent basis, should be undertaken. This is at the discretion of the local QA manager.
5.2.1.2 Prior to completion of the appropriate risk assessment(s), microbiological testing should be performed in accordance with Table I within PAR&D, and as deemed appropriate within Operation sites.
5.2.1.3 All other Non-sterile Dosage Forms:
Each lot of product should be tested for release, unless scientific justification that states otherwise is documented.
5.2.2 Method Development, Validation and Establishment
Results of validation, establishment and monitoring must be fully documented. R&D is responsible for the establishment of Specifications and Product Specific Methods based on the Pharmacopoeial Standards, which can be converted to product specific methods at the manufacturing sites.
5.2.3 Routine Analysis and Suggested Acceptance Criteria, Table I.*
Note: Table I includes a list of specified microorganisms for which acceptance criteria are set. The list is not necessarily exhaustive, and for a given preparation it may be necessary to test for other microorganisms depending on the nature of the starting materials and the manufacturing process. *Note: Table I was copied directly from the USP General Information Chapter <1111>. This chapter is provided for guidance, but is not mandatory. The same information is also presented in the EP as Table 5.1.4.1.
5.2.4 Results Reporting
Results must be retained for review on request during Regulatory Inspection. Certificates of Analysis must confirm compliance with the appropriate regulatory requirements. Test results should be provided by exception only if requested by the receiving site or if required by a Regulatory Authority.
5.2.5 Preservative Efficacy Testing Requirements
For products needing an antimicrobial preservative, acceptance criteria for preservative content may be appropriate. These criteria should be based on the levels necessary to meet the acceptance criteria for Antimicrobial Effectiveness in the applicable Pharmacopoeia at the end of the shelf-life. Release testing of the antimicrobial content should normally be performed. Under certain circumstances, in-process testing may suffice in lieu of release testing. Development data may be used to justify not including preservative effectiveness acceptance criteria during shelf life.