Florencia Cafisi, Chief of Analytical Development
Although the analytical procedure transfer of transdermal pharmaceutical products follows the same general guidelines as other dosage forms, it is necessary to consider some particular items that will help to optimize timelines and costs and, at the end of the day, will allow to achieve the objectives previously agreed between both laboratories. Not only the technical aspects of the method to be transferred and the characteristics of the material or product to be tested should be taken into account, but also we should highlight the importance of communication and teamwork, that are critical factors to perform the analytical transfer without issues, knowing the responsibilities of each laboratory and having in mind the needs and the expectations to be fulfilled.
This article describes, based on our own experience, some topics that may be helpful to be evaluated when facing an analytical procedure transfer; focusing on the final purpose, that is to obtain reliable results that reflect the quality of the products, independently of the laboratory and the personnel involved in the analysis.
The United States Pharmacopeia (USP) defines in Chapter <1224> the analytical procedure transfer, also known as analytical method transfer, as the documented process that qualifies a Laboratory (called receiving unit or laboratory) for using an analytical procedure originated in another laboratory (also referred as transferring, originating or developer unit or laboratory). As a result, the analytical procedure transfer will assure that the receiving unit has the procedural knowledge and the ability and resources necessary to execute the test in its facilities as intended and, thus, it is able to generate relevant GMP results.
Having in mind the role of the CDOs (Contract Development Organizations) in the outsourcing of pharmaceutical services, the analytical transfers mean a very important instance prior to the launching of the commercial product. This gains special relevance when we talk about transdermal pharmaceutical products, because sometimes they require specific quality control tests (USP <3> “Topical and Transdermal Drug Products – Product quality Tests”) that are not usually used for other types of pharmaceutical dosage forms.
The analytical transfer not only includes the technical aspect related with sharing theoretical and practical knowledge that are needed to reproduce the analytical procedure, but also considers other skills such as communication, adaptability and teamwork among the members of the participating laboratories. The existence of a robust and validated test method together with these soft skills, will help to successfully achieve the transfer goal.
Besides, the analytical transfer exercises are linked with the concept of technology transfer. On the one hand, the increase in outsourced manufacturing and analysis and, on the other, the upgrade of regulatory requirements, make it necessary for analytical laboratories to perform method transfers following good manufacturing practices (GMP). Thus, it is guaranteed that the quality controls that are carried out in the laboratories are reliable, regardless of the facilities and the human resources that participate in the analysis.
Analytical Transfer Classification
The USP describes the following types of Analytical Transfers:
· Comparative Testing
Both laboratories test the same samples and then statistical tools are applied for the comparative data assessment.
It is usually chosen for complex test methods that are in an advanced development stage, or methods that have been previously validated by the developer unit.
The receiving unit takes part of the analytical method validation performed at the transferring laboratory. It is usually done during the Precision assessment, either as intermediate precision (interlaboratory) or reproducibility (interlaboratory).
It is chosen for methods that are in the preliminary development stages or if the method has not been validated yet, because the receiving unit is involved in the method validation performed by the originating laboratory.
· Revalidation or Partial Validation
The receiving unit completely or partially executes the analytical validation of a method that was developed and validated by the originating laboratory.
· Transfer waiver
The justification for a waiver strategy must be well documented and can be considered in the following cases:
o The product’s composition/active ingredient concentration is similar to that of an existing product and is tested by procedures with which the receiving unit already has experience
o The analytical procedure being transferred corresponds to a compendial monograph; and in this case, only method verification should be done at the receiving unit
o The analytical procedure transferred is the same as or very similar to a procedure already in use at the receiving laboratory
o The personnel in charge of the development, validation or routine analysis of the product at the developer unit are moved and installed at the receiving unit.
As shown in the following Table, Amarin Technologies has been the Originating Unit in many Analytical Transfers of pharmaceutical transdermal products:
TYPE OF ANALYTICAL TRANSFER
Diclofenac gel 1%
Amarin Technologies QC
Amarin Technologies QC
Amarin Technologies QC
Amarin Technologies QC
The originating and the receiving units should agree on the best design for the analytical transfer. One of the main factors to be taken into account is the regulatory requirements, which may sometimes vary between different markets. There are specific resolutions about analytical validation and transfer, for example RDC 166/2017 issued by the Brazilian Agency (ANVISA) that clearly describe the guidelines to be followed. Furthermore, there are other points that should be considered such as costs, timelines, product complexity, experience of the receptor laboratory on the analytical technique, etc.
The beginning of the challenge: The pretransfer
During the pretransfer stage, the transferring unit is responsible for sharing with the receiving unit the information gathered during the development of the analytical method that will help to better understand the product and the procedure to be transferred. This exchange of technical information includes analytical development reports, validation reports, material safety data sheets reference chromatograms, product impurity profile, recommendations on brands of reagent or other supplies (filters, chromatographic columns), etc.
The receiving unit should write the analytical method following the procedures of its own Quality System and considering the description of the test method issued by the transferring unit. It is desirable that someone from the transferring laboratory reviews the final document previous to the beginning of the transfer exercise.
Considering that some laboratories do not have experience in the handling of transdermal patches, gels or creams, emphasis should be placed on the training of all the technical personnel of the receiving unit who are involved in the transfer exercise. This training may include the understanding of specific words related with transdermal delivery systems (e.g. release liner, backing film, cohesividad), definition of special requirements of equipment and supplies to be used, identification of the critical steps of sample preparation and information about solution stability and storage, calculations and expression of results, etc. The training must be properly documented and can be given through phone calls, videoconferences or via e-mail, face to face visits, exchanging of pictures or videos or any other tool that helps the receiving unit getting experience with the product and analytical procedure to be transferred.
It is important that during this stage, the receiving unit can reproduce the analysis to become familiar with the test procedure and fine-tune it at its own facilities using its instruments or equipment that should be properly calibrated or qualified. These preliminary trials consist of verifying compliance of system suitability requirements and helps to identify the necessity of adjustments to internal procedure; sometimes, testing a control or spiked sample can be useful. During the pretransfer, the analysts of the receiving unit ask their doubts or detect the possible difficulties that may arise during the analytical transfer; and working together with the development unit, they find clarifications or solutions to these troubleshooting.
Furthermore, the pretransfer encompasses, not only the technical approach, but also some definitions in connection with the supply of materials necessary for the transfer exercise, including the request of export/import licenses, permits for controlled substances and logistics issues such as shipping or special storage conditions of materials that will be used in the transfer or the definition of reference impurity standards suppliers. We suggest performing all these assessments in advance, because they may impact on the costs and timelines of the project.
Sometimes there are differences between the equipment (hardware and/or software) of both laboratories that may require amendments of the analytical procedure. These changes of the original test method must be adequately documented, including a risk assessment to evaluate the criticism and the impact of the modification on the validation status of the method to be transferred.
Moreover, it is possible that the receiving unit does not have the specific equipment for testing transdermal products and new instruments or accessories must be purchased. In these cases, the receiving unit should define the qualification requirements and the operational procedures for usage and maintenance and, It may be useful to have the technical assistance of the transferring unit that, based on its experience, can help to define some details of this new acquisition.
Once again, the importance of GMP documentation
Once the pretransfer has been completed and the type of transfer has been agreed between the parties, it is time to define each laboratory responsibilities, the experimental design (including amount of batches to be tested, number of replicates, type of samples to be analyzed, etc.), results to be reported (it is recommended to include a template for data submission), procedure for calculations and statistical assessments and acceptance criteria. It is also important to describe the procedure to be followed in case of non-compliance or deviations, since both laboratories should participate in the investigation of the root cause and the corresponding corrective and preventive actions. All this information is described in the transfer protocol that should be approved by both laboratories before the beginning of the analytical trials.
Usually, when the transfer is successfully completed, the receiving unit is responsible for writing the transfer report submitting the results in relation with the acceptance criteria , along with conclusions that confirm that the receiving unit is now qualified to run the procedure. This report should be also approved by the transferring unit that will perform an overall and detailed assessment of the raw data and the final results, verifying the achievement of the analytical transfer aim.
The pathway towards a successful analytical transfer
In conclusion, the analytical method transfer complements and accompanies the validated status of a test method. It should follow the Quality System procedures and it allows the compliance of the regulatory requirements from the country where the product will be sold. For transdermal dosage forms, it usually represents a greater challenge, because the receiving unit may be giving its first steps in testing this type of pharmaceutical products, which means a learning and increases the expectations.
The successful results of a method transfer depend, among other factors, on an clear and dynamic communication between the participants, the definition of predefined objectives and responsibilities, the training of the personnel, the characteristics of the equipment and the redaction of complete and clear documentation, explaining some practical details that are relevant for a correct understanding of the product and the analytical procedure to be transferred.
Amarin Technologies has a team of collaborators and professionals with wide experience in performing analytical method transfers with local and foreign companies. Our commitment is to create a space of dialogue, providing technical assistance to other laboratories so that the analytical methods developed at Amarin Technologies are executed successfully in other laboratories obtaining reliable results that reflect the quality of our products.
· USP <1224> “Transfer of analytical Procedures” <3> “Topical and Transdermal Drug Products – Product quality Tests”)
· Handbook of Modern Pharmaceutical Analysis, Chapter 14: Analytical Methodology Transfer, Stephen Scypinski
· Transfer of Analytical Procedures: Position Paper, M. Limerger, J. Ermer, K. Lis, T. Faust, I. Astner, D. Behrens, H. Hower-Fritzen y H. Watzig
· The Central Role of Analytical Method Development and Validation in Pharmaceutical Development, Robert W. Lee PhD y Laurie Goldman. Life Science Connect
· Transfer of Analytical Procedures according to the New USP Chapter <1224> – An Overview, Gajanan M. Naik, Veerendra Yeligar. International Journal of Pharmaceutical Research Vol. 4. No.2. pp 599-601 April-June 2012
· Pharmaceutical Research and Manufacturers Association Acceptable Analytical Practice for Analytical Method Transfer; Stephen Scypinski, Darryl Roberts, Mary Oates, and Joseph Etse Pharmaceutical Technology March 2002
· Resolution ANVISA Nro. RDC 166 de 24-Jul-2017
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