Quality Control – Overview and Key Principles

Quality Control Principles:

Quality Control (QC) involves sampling, setting specifications, testing, as well as the organization, documentation, and release procedures. These steps ensure that necessary and relevant tests are conducted, and materials are not approved for use, nor are products released for sale or distribution, until their quality has been deemed satisfactory. QC is not limited to laboratory work but extends to all decisions impacting product quality. The independence of QC from production is essential for its proper functioning.

General Overview:

1.0 Any entity holding a manufacturing authorization should have a Quality Control Department. This department must be independent from others and led by a qualified individual with sufficient experience. This person should have access to one or more control laboratories. Sufficient resources must be available to ensure the effective execution of all QC activities.

1.1 The QC Department is also responsible for establishing, validating, and implementing QC procedures. Additionally, it oversees the control of reference and/or retention samples of materials and products (when applicable), ensures proper labeling of materials and products, monitors product stability, investigates quality-related complaints, and more. All tasks should be performed according to written procedures and documented when necessary.

1.2 Finished product assessment should take into account factors such as production conditions, results of in-process testing, a review of manufacturing (including packaging) records, compliance with the Finished Product Specification, and examination of the final packaging.

1.3 QC personnel should have access to production areas to conduct sampling and investigations where necessary.

Good Laboratory Practices in Quality Control:

1.4 Laboratory facilities and equipment should meet both general and specific requirements for a QC area. Microbiological labs, in particular, should be designed to minimize the risk of cross-contamination. Laboratory equipment should not be routinely moved between high-risk areas to avoid accidental contamination.

1.5 The personnel, premises, and equipment in the laboratory must be suitable for the tasks based on the nature and scale of the manufacturing processes. While outsourcing testing to external laboratories is acceptable for specific reasons, this should be documented in QC records.

Documentation:

1.6 Laboratory documentation must adhere to established principles. Key documents should include:

• Specifications
• Procedures covering sampling, testing, recordkeeping (including test worksheets and/or lab notebooks), recording, and verification
• Procedures for investigating Out Of Specification and anomalous results, as well as Out Of Trend data
• Calibration/qualification records for instruments and equipment maintenance
• Test reports or certificates of analysis
• Environmental monitoring data (e.g., air, water, and other utilities) if required
• Validation records for testing methods, where applicable

1.7 Any QC documentation related to batch records must be retained along with the batch documentation.

1.8 Some data, such as test results, yields, and environmental controls, should be recorded in a way that allows for trend analysis. Any data outside acceptable trends or specifications must be investigated.

1.9 Besides batch documentation, other raw data such as laboratory notebooks and records should be retained and easily accessible.

Sampling:

Sampling should be conducted and documented in accordance with approved written procedures that specify:

• Sampling methods
• Equipment to be used
• Amount of sample to be taken
• Instructions for dividing the sample
• Sample container type and condition
• Sample container identification
• Special precautions, especially for sterile or hazardous materials
• Storage conditions
• Cleaning and storage instructions for sampling equipment

2.0 Samples should be representative of the batch from which they are drawn. Additional samples may be collected from the most critical parts of the process (e.g., start or end). The sampling plan should be well-justified.

2.1 Sample containers must be labeled with the contents, batch number, sampling date, and the source containers. They should be handled to minimize mix-ups and protect the samples from adverse conditions.

Testing:

2.2 Testing methods should be validated. If a laboratory is using a method that was not initially validated by them (e.g., compendial methods), it must verify the method’s suitability. All testing outlined in the marketing authorization or technical dossier should be conducted according to approved methods.

2.3 Test results should be recorded, monitored for trends, and checked for consistency. All calculations should be carefully reviewed.

2.4 Test records must include:

• Material/product name, and dosage form (if applicable)
• Batch number and, where relevant, the manufacturer/supplier
• References to specifications and testing procedures
• Test results, including observations, calculations, and reference to certificates of analysis
• Test dates
• Initials of individuals performing the tests
• Initials of individuals verifying the tests and calculations (if applicable)
• Clear approval or rejection statement, along with the dated signature of the responsible person

2.5 All in-process controls, including those by production staff, should be carried out according to QC-approved methods and documented.

2.6 Extra attention should be given to the quality of laboratory reagents, solutions, glassware, reference standards, and culture media, which must be prepared and controlled in line with written procedures.

2.7 Reference standards should be certified, qualified, and verified for suitability.

2.8 Culture media should be prepared according to the manufacturer’s guidelines unless scientifically justified. Their performance must be verified before use.

2.9 Reagents, solutions, reference standards, and culture media must be marked with the preparation and opening dates and the preparer’s signature. Their in-use shelf life must be documented and scientifically justified. Expiry dates and specific storage conditions should be labeled for unstable reagents and culture media. For volumetric solutions, the last standardization date and current factor should also be noted.

3.0 The date of receipt for substances used in testing (e.g., reagents, solutions, reference standards) should be indicated on the containers. Proper storage and usage instructions should be followed. In some cases, identification tests or other assessments may be required before using reagent materials.

3.1 Animals used in testing must be quarantined when necessary and maintained in conditions ensuring their suitability for the intended tests. Adequate records showing their usage history should be kept.

3.2 Microbiological media and strains should be decontaminated and disposed of to prevent contamination and residue buildup. The shelf life of microbiological media should be documented, established, and scientifically justified.

Ongoing Stability Programme for Medicinal Products

Introduction

The ongoing stability programme for medicinal products is an essential aspect of ensuring the safety, quality, and efficacy of the product throughout its shelf life. This programme involves continuous monitoring of the medicinal product after it has entered the market, with the goal of detecting and addressing any potential stability issues that could arise. Such issues may include changes in the levels of impurities or alterations to the dissolution profile. The purpose of this ongoing stability programme is to ensure that the product remains within the established specifications under the storage conditions outlined on the label.

Purpose of the Ongoing Stability Programme

The primary objective of an ongoing stability programme is to monitor the stability of the product throughout its shelf life. This allows the manufacturer to confirm that the product remains effective and safe for use, and will continue to meet the established specifications when stored under the conditions specified on the product’s label. As the product is marketed, it undergoes routine stability testing to detect any changes in physical, chemical, microbiological, or biological characteristics. It also enables manufacturers to identify any potential degradation or impurity formation over time.

Scope of the Ongoing Stability Programme

While the ongoing stability programme mainly applies to the medicinal product in the package in which it is sold, consideration should also be given to bulk product and intermediates used during the manufacturing process. Bulk products, in particular, may be stored for extended periods before being packaged, or they may be shipped from a manufacturing site to a packaging site. In these cases, it is important to assess how such storage and transportation conditions affect the stability of the packaged product. The programme should also include stability assessments for intermediates that are stored and used over long periods, as they may influence the final product’s stability.

Studies conducted during product development, such as those on reconstituted products, are typically sufficient and do not require ongoing monitoring. However, if necessary, the stability of reconstituted products can also be monitored through the ongoing stability programme.

Protocol for the Ongoing Stability Programme

To ensure the effective implementation of the ongoing stability programme, it must be clearly outlined in a written protocol. The protocol should specify how stability will be monitored and the methodology for testing. This includes the equipment to be used, such as stability chambers, which must be properly qualified and maintained.

The protocol should extend through the entire shelf life of the product and should include several key components:

• Number of batches: The programme should specify the number of batches per strength and for different batch sizes, where applicable.
• Test methods: It should detail the physical, chemical, microbiological, and biological tests that will be used to evaluate product stability.
• Acceptance criteria: The protocol must outline the acceptance criteria for stability, which serve as benchmarks for determining whether the product remains within its specifications.
• Reference to test methods: Clear references should be made to the test methods and standards employed during the stability testing.
• Container closure systems: A description of the packaging systems used for the product must be included.
• Testing intervals: The time points at which stability testing will occur should be defined, ensuring adequate data is collected over the product’s shelf life.
• Storage conditions: Testing should be carried out under conditions that are in line with ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) and VICH (International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products) recommendations for long-term testing. This should align with the storage conditions detailed on the product’s label.
• Product-specific parameters: If applicable, the protocol should include any other specific parameters that are relevant to the stability of the particular medicinal product.

Adjustments to the Stability Programme

The ongoing stability programme can differ from the initial long-term stability study protocol that was submitted as part of the marketing authorisation application. However, if changes are made, these must be justified and documented. Examples of such changes could include the frequency of testing or adjustments made in response to updated ICH/VICH guidelines. The programme may be updated to accommodate any new recommendations or regulations that arise after the initial submission of the marketing authorisation dossier.

Frequency of Testing and Batch Inclusion

The number of batches selected for testing and the frequency of testing should be sufficient to provide meaningful data for trend analysis. As a general rule, at least one batch of each product strength and primary packaging type should be included in the stability programme each year. If no products are manufactured in a particular year, this condition does not apply. If the product requires animal testing, and no suitable alternatives are available, the testing frequency should be determined using a risk-benefit approach.

The principles of bracketing and matrixing can be applied in the protocol, provided they are scientifically justified. These approaches allow for a more efficient testing programme by reducing the number of required test samples while still providing valid data.

Special Circumstances Requiring Additional Stability Monitoring

There are situations where additional batches should be included in the ongoing stability programme. One example is when significant changes or deviations occur in the manufacturing process or packaging. Any reworking, reprocessing, or recovery operations also require special consideration and inclusion in the stability programme, as these processes may alter the stability profile of the product.

Reporting and Availability of Stability Data

The results of ongoing stability studies should be made available to key personnel involved in the product’s quality management and oversight, especially the Qualified Person(s) responsible for ensuring the product’s compliance with regulatory standards. If stability studies are carried out at a location other than the site of manufacture, there must be a written agreement between the parties involved to ensure proper coordination. Additionally, stability results must be available at the manufacturing site for review by the relevant regulatory authorities.

Any out-of-specification results or significant atypical trends in the stability data should be investigated promptly. If any result falls outside of the acceptable criteria or if there is a significant negative trend, these should be reported to the competent authorities. The potential impact on batches already in the market should be assessed and communicated to the authorities in accordance with the relevant guidelines.

Data Summary and Review

A summary of all data generated from the ongoing stability programme, including any interim conclusions, should be maintained in a central record. This summary should be reviewed periodically to ensure that the product continues to meet its stability requirements over its shelf life.

Technical Transfer of Test Methods

As part of the ongoing stability programme, it may be necessary to transfer test methods from one laboratory to another. Before beginning this transfer, the transferring site must verify that the test methods in use are in compliance with those outlined in the Marketing Authorisation or relevant technical dossier. The original validation of the test methods should be reviewed to ensure they meet current ICH/VICH requirements. Any gaps identified during this review should be addressed before initiating the transfer process.

A gap analysis is an essential part of this process, and any supplementary validation needed should be performed and documented prior to the commencement of the transfer. The transfer of test methods from one laboratory to another should be described in a written protocol. The protocol should outline several important parameters, including:

• Identification of test methods: Clear identification of the test methods being transferred must be provided.
• Training requirements: Any additional training needed for personnel involved in the transfer should be identified.
• Standards and samples: The protocol should specify which standards and samples will be tested by both laboratories to ensure consistency and accuracy in the transfer.
• Special storage and transport conditions: If applicable, the protocol should detail any special conditions for the transport or storage of test items.
• Testing to be performed: The specific testing that needs to be conducted during the transfer should be outlined.
• Acceptance criteria: The criteria used to evaluate the success of the transfer should be based on the current validation studies and must align with ICH/VICH guidelines.

Deviations from the protocol should be investigated and documented, and any differences that may affect the transfer process should be addressed before completing the transfer.

Conclusion

In summary, the ongoing stability programme is a critical component in ensuring the long-term quality, safety, and efficacy of medicinal products. By continuously monitoring the product throughout its shelf life and addressing any stability issues that arise, manufacturers can ensure that the product remains within the established specifications. The programme should be described in a comprehensive protocol, and regular testing and review should be conducted to ensure compliance with all relevant regulations. Special circumstances, such as changes in the manufacturing process or packaging, require additional monitoring, and the results of the programme should be made available to key personnel and regulatory authorities as necessary. Furthermore, the technical transfer of test methods must be carefully managed to ensure the accuracy and consistency of the stability testing across different laboratories.