By Grant Mordue
Many organic solvents are used during the manufacturing of active pharmaceutical ingredients (APIs) and associated intermediates. Solvents may be supplied fresh in drums or in bulk, e.g., using tanks transported by road or rail. To reduce costs and provide flexibility, manufacturers and distributors use multipurpose tankers, which are used for a variety of ingredients, including solvents. This presents a risk of cross-contamination that might not be detected when the solvent is tested before offloading into a manufacturing site distribution system.
When the API is washed with solvent prior to drying, contamination from the solvent could remain in the dried API. The final testing of the API is not designed to detect any unexpected contamination and therefore the contaminated API could be released for use. Alternatively, unexpected unknown peaks could be detected during chromatographic analysis, triggering investigation, potential manufacturing downtime, and probable costly rejection of the API, for which there may be no possible reprocess or rework option. Careful management of the solvent supply chain can help prevent this type of problem. This article explores the risks and 11 mitigation options available to API manufacturers.
1. Adopt a Categorization For Critical Solvents.
The existence of registered starting materials (RSMs) and critical raw materials (which contribute to the structure of the final API) is well known, and controls are expected to be in place to only source these from approved suppliers, which after risk assessment could require an audit prior to approval and use. However, where an API is washed with a solvent prior to drying and offloading, if the quality of this solvent is compromised, there is a high risk that the API will be adulterated and that this contamination might not be detected during the final testing of the API. Adopting a categorization describing “critical solvents” should therefore be considered and subject to controls similar to those described above for RSMs and critical raw materials.
2. Map the Critical Solvent Supply Chain – Manufacturer Vs. Distributor.
It’s important to understand exactly where (and by whom) the solvent is first manufactured and, preferably, to understand the synthetic process used to manufacture the solvent. This will determine the impurity profile for the solvent and could also influence the level of other molecules present, e.g., water and other solvents and process components.
The supply chain, from the initial site of manufacturing to delivery at the site of use, should be researched, mapped, and evaluated. The manufacturing site might supply the solvent to a bulk distribution location, which stores the solvent in large tanks and offloads a quantity to a transportation tank when an order is received. This is typical if the bulk solvent is received by ship into a bulk distribution center. Similarly, a distribution site could fill the solvent into drums for storage and supply as orders are received.
Each stage in the supply chain should be assessed for the risk of introducing contamination to the solvent. This risk assessment might indicate that audits are required to evaluate the risks and the reliability of the controls in use at the distribution locations to prevent cross-contamination during offloading, storage, and loading into the final tanks for delivery.
3. Become Dedicated To Reducing The Risk Of Contamination.
Bulk solvents supplied in road or rail tanks should use tanks dedicated to use for only that specific solvent whenever possible. This reduces the risk that contamination might be introduced by a failure to adequately clean a multipurpose tank before reuse. Unfortunately, unless a large volume of solvent is being purchased, suppliers rarely offer this without additional cost; however, the receiving site should consider purchasing a tanker dedicated to its use or paying more to guarantee that only dedicated tanks will be used. The solvent will always cost less than rejection of adulterated API.
4. Examine The Multipurpose Option Carefully.
If using multipurpose tankers cannot be avoided, it is important to carefully examine how the tanks are cleaned after use and how the cargoes are allocated to the tanks that could deliver the critical solvent required.
I remember an example of a failure to adequately manage cargo allocation and cleaning, that was identified when a pre-offload sample of an organic solvent received at an API manufacturing site became cloudy when diluted with water. The IR spectroscopy analysis confirmed that the delivery was contaminated and, fortunately, it was not offloaded into the site storage and distribution system. The investigation revealed that the cargo prior to the previous cargo had been a material that was not soluble in the previous cargo but was soluble in the critical solvent in the current delivery. This lack of solubility also caused a failure in the aqueous cleaning method used to remove this cargo. As a result, the facility used to clean and manage the road tankers was audited and an approved prior cargo list was put in place with the supplier. Only organic solvents, which are detectable using the site GC testing applied before offloading, were approved as the cargoes allowed for distribution in the tanks allocated for use in supply to the site.
5. Review And Agree On Banned Cargoes.
When multipurpose tanks are used, it’s important to meet with the supplier prior to approval to review, discuss, and agree which cargoes are allowed to be used with the tanks used to supply the critical solvent. These should be restricted to cargoes that are easy to remove and are detectable using the testing performed before offloading into the site storage and distribution system. A list of “banned cargoes” should be formally put in place and incorporated into the checks performed by personnel when receiving critical solvents at the API manufacturing site.
6. Review The Certificates Of Cleaning Before Sampling The Solvents.
It’s typical that solvents delivered in multipurpose tanks are received with an accompanying Certificate of Cleaning. This must be checked carefully by trained personnel before the solvent is sampled for testing prior to connection to the site offloading system. Important details include:
- The correct description of the solvent supplier, as listed on the site approved supplier index.
- The name and location of the cleaning station used.
- The correct unique identification code for the tank actually received on-site, i.e., the solvent storage tank, distinct from the registration of the vehicle towing the tank.
- The correct description of the delivered solvent, in-line with the exact description of the site ordering and inventory management system.
- The clear description of the previous cargo (for comparison with the list of “banned cargoes”).
- The clear description (which might be via the entry of an index code) of the cleaning carried out to remove the last cargo.
- The name and signature of the person who performed the cleaning. This cleaning might also have included the hose carried with the tanker for use when offloading at the user site, if required. In most cases this hose is not used by the site as it is preferable to use hoses dedicated for this use at the site.
- The name and signature of the person who checked and confirmed that the tank was clean and dry before use for the delivered solvent.
- The name and signature of the driver who delivered the solvent to the site.
In Europe, it is common that the certificate of cleaning follows an agreed upon “ECD” format. More information about this can be found at https://www.eftco.org/.
7. Understand That Not All Certificates Of Analysis Represent The Quality Of The Delivered Solvent
A Certificate of Analysis (C of A) or Certificate of Conformity (C of C) is usually also provided with each delivery. It’s important to understand how this relates to the actual quality of solvent delivered to the site each time. The best case is that the solvent in the actual delivery tank was sampled, tested, and certified by the manufacturer/supplier prior to transport for delivery; however, this might not be the case.
The certificate might reflect the results following sampling of the bulk tank used to fill the transportation tanker and therefore not fully representative of the quality of the solvent actually delivered to the site. This result might be an average of results obtained over a period of time, e.g., a C of C, or it might be the last result obtained following the sampling of the bulk tank, i.e., a C of A. This is where an audit of the solvent distribution facility can be used to determine exactly how testing and certification are performed, leading to an agreement as to what needs to be done to adequately manage the testing and certification required.
8. Perform A Pre-Offload Sample Of The Critical Solvent.
First, the documentation, including the C of A or C of C and the certificate of cleaning, must be checked by trained personnel to confirm completeness and correctness before the delivery is allowed to move into position ready to commence offloading. The delivery tank should not be connected to the site distribution system at this stage.
Once the documentation has been formally signed as complete and correct, a sample of the solvent should be obtained for pre-offload testing. The sample is most often taken by dipping a sample container into the solvent through a manway on the top of the tanker. This procedure exposes the solvent to the environmental conditions at the time of the sampling; therefore, protection must be provided to prevent the ingress of rain, dust, or other weather and environmental related contamination during the sampling operation. If a sampling manifold is used, which is stored at the site and connected for use and cleaned afterward, the cleanliness and dryness of this manifold must be confirmed (and thus recorded) prior to use.
The pre-offload sample must be tested by QC for the critical specification parameters that will confirm the identity and integrity of the solvent contained in the tank. This testing must be designed to identify if the delivery is contaminated with, e.g., water, other solvents known to be potentially present in the supply chain, particulates, or suspended matter.
It’s important that the test results are formally communicated and that this communication is recorded between QC and the personnel who will then connect the transport tanker to the site solvent offloading, storage, and distribution system. The date and time of this connection must be recorded and must be later than the date and time of the communication of the test results. Some sites also have locks preventing the opening of the valve that allows the flow of the delivered solvent into the site system. Only QC personnel have the key(s) to the locks to ensure that offloading cannot take place until the testing has confirmed acceptable quality.
9. Use Proper Hosing.
It’s preferable not to use the hosing carried by the tanker and instead use the site’s hosing dedicated to offloading into the site storage and distribution system. The best practice is to dedicate a unique hose for each received solvent, with each clearly and uniquely marked with the solvent’s details. Each hose must be cleaned and dried after use and stored with both ends securely closed/capped (the caps are dedicated to each hose and usually securely fixed to the hose). For storage, the clean, dry, and capped hoses should be stored on a rack off the ground or preferably in a tube to provide protection from the environment.
10. Record Offloading Activities.
Connection to the site offloading system must only take place after formally recording that QC has successfully completed the analysis of the pre-offload sample. The trained offloading personnel must ensure that the offloading hose is connected to the correct manifold connection, which must be clearly labelled with the identity of the solvent. Care should be taken to avoid or clearly distinguish between similar solvents, e.g., 2-propanol (iso-propanol) and n-propanol (propanol), etc., located at or near to the same offloading point, to avoid potential confusion and error. The connection time and start and end of offloading times must be recorded, together with the signature of the trained personnel performing the operation(s). After offloading, the hose must be cleaned, dried, capped and securely stored and the offloading point must be capped and locked as stated in the relevant SOP.
11. Don’t Forget About Routine Testing.
Following the completion of the pre-offloading testing, QC should complete the remaining specification testing on the sample without delay. The full set of results should be compared to the results reported on the C of A or C of C received with the delivery and any anomalies should be investigated. There may be differences due to analytical variation between the two laboratories performing the testing; however, any significant differences could indicate a change in the quality of the solvent between the testing by the supplier and testing by the receiving site.
The overall specification compliance of the bulk solvent stored in the site distribution system should not change over time; however, it is common practice to sample this supply at intervals to confirm continuous compliance, as the volume in the system will comprise multiple deliveries over time. Again, there shouldn’t be any significant difference between the quality of the solvent in the distribution system and the quality received with each delivery.
In conclusion, the control of the solvent used to wash final API prior to drying and offloading should be carefully managed to prevent potential solvent supply chain-related contamination from adulterating the API. Care should be taken when selecting suppliers and the transportation conditions required. Receiving site personnel must ensure that the proceduralized controls have been followed and that a representative sample of the delivered solvent has passed carefully selected testing before offloading the solvent into the site storage and distribution system. Site QA should audit the solvent supply chain and check that the required controls are being followed.
About The Author:
Grant Mordue is the director of Pro-Active GMP Consulting Ltd., a U.K.-based consultancy founded in April 2020 to help companies to successfully implement a proactive level of quality management and cGMP compliance. Mordue has more than 30 years of management experience across the cGMP compliance of manufacturing and supply operations at local (national) and global levels, including the management of regulatory inspections. He has a BSc (Hons) degree in applied chemistry and is a Chartered Chemist and Member of the Royal Society of Chemistry in the U.K. You can connect with him on LinkedIn.