A Guide to GMP Regulations – Part 3: Quality Control

14 February 2022

This is the third part in a 4-part blog series on A Guide to GMP Regulations. Part 1: What is GMP? Can be found here and Part 2: GMP Personnel and Documentation can be found here.

Good Manufacturing Practices (GMP) are a set of systems in place to ensure that products can be produced consistently to a high standard and are controlled to the standards appropriate for their intended use. GMP is intended to regulate both the production, and quality control of products.

As mentioned in A Guide to GMP Regulations – Part 2: GMP Personnel and Documentation, a Quality unit should be present in every GMP manufacturing facility to confirm compliance with good manufacturing practices. Quality control involves the setting and monitoring of specifications and release procedures, by ensuring that the necessary and relevant tests are carried out. It is essential that materials are not released for use, or products released for supply, until their quality has been proven satisfactory.

Quality Control laboratories

Quality control laboratories should be provided for testing and approval (or rejection) of components, drug product containers, in-process materials, and drug products. These laboratory facilities may include contract testing laboratories if facilities on the manufacturing site are not adequate. If contract testing laboratories are used, however, these should be fully audited, and their use should be stated in the quality control records. Laboratory controls and tests should be detailed in procedures as with manufacturing procedures, and they must be based on scientifically sound methods, and have appropriate specifications and procedures.

Sterility and endotoxin testing

Some of the most important quality control tests performed on a batch are the final product sterility and endotoxin (pyrogen) tests. If a product is to be used as a sterile, or pyrogen-free product, it must be shown to be in fact sterile, or pyrogen free through documented, scientifically sound testing.

“For each batch of drug product purporting to be sterile and/or pyrogen-free, there shall be appropriate laboratory testing to determine conformance to such requirements” – FDA Guidance for Industry (Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice)

These tests should be performed on a representative sample of the batch of product, meaning that a number of units which accurately portray the materials being samples should be tested. A detailed sampling plan should be documented to ensure that representative samples are taken, and it is important to ensure that samples are taken at the beginning, middle and end of processing, and also following processing interventions or excursions. This is to ensure that any potential contamination from these excursions is detected, as well as the highest risk times being the start and end of processing.

Representative sampling for sterility and pyrogen testing limits the ability of these tests to detect contamination due to the small sample sizes used – the samples tested cannot be distributed, and therefore the sensitivity of these tests is limited. Because of this limited sensitivity, any positive results should be considered a serious issue which requires thorough investigation.

Process simulations

As sterility testing only tests a proportion of each batch, sterility of an entire batch cannot be confirmed by this testing. To ensure the manufacturing process is producing sterile drug products, all aseptic processes should be fully validated using an aseptic process simulation.

When processing procedures are initially qualified, process simulations should be repeated enough times to ensure that results are consistent and meaningful. This is important as multiple runs with different results may indicate that a process is not in control. Following initial qualification, routine process simulations should be performed (at least twice a year) to evaluate the state of control of the aseptic processes. All personnel authorised to enter processing rooms during manufacture should also participate in a process simulation at least once a year, and their participation should reflect the nature of their role during routine production.

These process simulations mimic the process of manufacturing the product using a microbial growth medium in the place of the product. The media used should be tested to show that it can promote the growth of all standard pharmacopeial organisms, and, where determined to be required, growth of production environmental isolates.

They should incorporate worst-case activities and conditions which could jeopardise the sterility of a final drug product, however they should not be used to justify practices which pose unnecessary contamination risks. They should, instead, be representative of the conditions under which actual manufacturing operations are conducted.

All process simulation runs should be observed by the Quality department to ensure compliance is maintained, and environmental monitoring should be performed as it would be during normal product manufacture.

If contamination is detected in a process simulation, it must be investigated extensively, as this may indicate a failure in the sterility assurance. Recoveries should be identified to species level, and the investigation should include an impact assessment to all drugs produced since the last successful simulation. Following investigation, once corrections have been implemented, further process simulations should be run to confirm that deficiencies detected have been corrected, and the process has returned to a state of control.

Product Quality Reviews

As well as confirming the release of materials and products, Quality departments must ensure that regular product quality reviews are performed for all authorised products. These reviews should confirm that the processes for manufacture and testing are performed consistently, and that current specifications remain appropriate. These reviews should consider previous reviews, as well as a review of all batches produced, changes made to processes, analysis or equipment and utilities, as well as assessment of stability monitoring and all quality-related aspects of the product. The results of the review should then be evaluated and assessed as to whether any inconsistencies are discovered, and whether corrective and preventive action or any revalidation should be undertaken.

The Quality Control Department are also responsible for establishing and validating quality control procedures. These procedures should be in place to ensure the quality of the product throughout the manufacturing process, but also during the product lifecycle – reference and retention samples are stored by the department, as well as ensuring the correct labelling of products. Stability should also be monitored over the product’s shelf-life and beyond, to ensure that they remain fit for their intended use, even after being distributed away from the manufacturing facility.

Procedures should also be in place for sampling and testing of products, intermediates, and containers. These procedures, and testing results, should be maintained and reviewed regularly by the quality control department to ensure that they meet specifications and are being performed correctly. These reviews should form a part of the certificates of analysis which are supplied during the release of the product.

Assessment of results

Quality Control should also include a procedure for investigating out of specification and out of trend results, to ensure a root cause analysis is performed and any corrective or preventative actions are implemented as required, as well as maintenance, calibration and validation procedures and data from these processes, to ensure that all facilities and equipment are validated and maintained correctly. There should also be procedures in place for environmental monitoring of air, water and other utilities, and the data from this monitoring should be readily available to the quality control department.

Results of process simulations and environmental monitoring of routine batch manufacture should be analysed together, according to the new Annex 1 guidance. Environmental monitoring data from process simulations can be used to evaluate conditions within the production areas and can also be used to aid in investigations into contamination events.

Analysing all of this data concurrently can be challenging, with high volumes of data produced from both process simulations and routine batch manufacture. Data is often stored in difficult to understand formats, and raw data may be archived and difficult to access. However, systems such as SmartControl EM allow all data to be stored in one easily accessible location, and allows the simple generation of graphs, reports, and analysis tools, as well as performing automatic trend analysis of data as it is input. Systems such as SmartControl EM are becoming more common in Quality departments to ensure the compliant and efficient data storage and analysis of all data in one place.