Method transfer between 2 GMP labs
1. Analytical Method Transfer:
As per the USP, the transfer of an analytical method is defined as the documented process that qualifies a laboratory (receiving laboratory) to use an analytical method that originated in another laboratory (transferring laboratory), whether that is internal or external to the receiving laboratory.
These two types of laboratories can have varying relationships. As mentioned above, the two laboratories can be external or internal to one another.In other words, the method may have been developed by a manufacturing facility (internal) and be sent to an external (contracted) laboratory for testing.
Additionally, the method can be transferred from an internal laboratory to another internal laboratory of the same facility (i.e. a Product/Process Development laboratory to Quality Control laboratory)1.
2. Not as straightforward as Implied:
The development of AMTs is neither easy nor simple. According to the U.S. Food and Drug Administration’s (FDA) Analytical Procedures and Methods Validation for Drugs and Biologics: Guidance for Industry, “An analytical procedures should be described in sufficient detail to allow a competent analyst to reproduce the necessary conditions and obtain results within the proposed acceptance criteria.”
Although this statement implies that the process should be relatively straightforward, it does not mean AMTs are as simple as providing the analytical method to the new testing site and assuming it will be able to execute the method successfully.
➢ procedures and
➢ even interpretations of an analytical procedure can lead to preventable AMT failures.
To ensure successful AMTs and avoid preventable failures, it is critical to develop a well-defined transfer plan with open lines of communication2.
3. Transfer Process:
➢ In any technology transfer (process) there are two primary parties involved:
a. the “sending unit” (SU): The SU, also known as the transferring laboratory, is the source or originating laboratory for of the analytical procedure
b. the “receiving unit” (RU): The RU, also known as the receiving laboratory, is the internal or external laboratory being qualified on the analytical procedure2.
➢ Transfer of analytical methods should accommodate all the analytical testing required to demonstrate compliance of the product to be transferred with the registered specification.
➢ Analytical methods used to test pharmaceutical products, starting materials, packaging components, and cleaning (residue) samples, if applicable, should be implemented at the testing laboratory before testing of samples for process validation studies is performed by the RU. Process validation samples may be tested at the RU, the SU or a third laboratory.
➢ A protocol defining the steps should be prepared for transfer of analytical methods. The analytical methods transfer protocol should include
a) a description of the objective,
b) scope and responsibilities of the SU and the RU;
c) a specification of materials and methods;
d) the experimental design and acceptance criteria;
e) documentation (including information to be supplied with the results, and report forms to be used, if any);
f) procedure for the handling of deviations;
h) signed approval; and
i) details of reference samples (starting materials, intermediates, and finished products).
➢ Appropriate training should be provided and all training activities and outcomes should be documented3.
4. Responsibilities of Sending Unit:
The SU’s responsibilities for the transfer of analytical methods are to:
➢ provide method-specific training for analysts and other quality control staff, if required; ➢ assist in analysis of QC testing results;
➢ define all methods to be transferred for testing a given product, starting material or cleaning sample; define experimental design, sampling methods and acceptance criteria;
➢ provide any validation reports for methods under transfer and demonstrate their robustness
➢ provide details of the equipment used, as necessary (part of validation report, if available) and any standard reference samples;
➢ provide approved procedures used in testing; and
➢ review and approve transfer reports3.
Responsibilities of Receiving Unit:
The RU’s responsibilities are to:
➢ review analytical methods provided by the SU, and formally agree on acceptance criteria before execution of the transfer protocol;
➢ ensure that the necessary equipment for QC is available and qualified at the RU site. The equipment used by the RU during the analytical transfer should meet appropriate specifications to ensure the requirements of the method or specification are met;
➢ ensure that adequately trained and experienced personnel are in place for analytical testing;
➢ provide a documentation system capable of recording receipt and testing of samples to the required specification using approved test methods, and of reporting, recording and collating data and designation of status (approved, rejected, quarantine);
➢ execute the transfer protocol;
➢ perform the appropriate level of validation to support the implementation of the methods; and
➢ generate and obtain approval of transfer reports3.
6. Type of AMT transfer:
As defined in USP 1224, there are many acceptable approaches to accomplish an analytical method transfer. Several factors should be evaluated when determining which type of transfer is appropriate for the product/situation:
- Instrumentation/method changes
When performing this evaluation, it is important to note that some of these factors can have negative impacts on other factors. For example, designing an AMT to perform the transfer in the shortest time frame may not be the most cost-effective manner. It is therefore important to understand key drivers for the transfer and potential impacts of a proposed transfer approach2.
A. Comparative testing:
The most common method for AMT is comparative testing. As defined in USP 1224, comparative testing requires the analysis of the same set of samples by both the SU and the RU.
- Choosing the correct, or appropriate, samples can be critical to ensure a successful transfer.
- Utilizing multiple lots if available is recommended; relying on a single lot may be risky, especially if there is some lot-to-lot variability observed and/or the process involves a drug product method.
- For impurity methods, ensure that the samples contain the impurities detailed in the method; if the samples do not, the use of aged/expired samples, spiked samples or forced degraded samples is highly recommended.
- Clinical trial material that is actively being used and commercial material on the market should not be used in the transfer2.
B. Co-validation or multisite validation
With the co-validation or multisite approach, the RU executes some aspects of method validation. This typically involves reproducibility testing in conjunction with the SU.
Although this can be an efficient way to transfer the method, it can lead to delays in finalizing the validation report. If, for example, failures are encountered by the RU during its portion of the testing, validation will be delayed until all transfer issues are resolved 2.
Re-validation or partial revalidation is also considered acceptable for AMTs. It is commonly performed when the SU is unable to participate in the transfer activities. This process generally requires more time and is more expensive compared with the other modes of transfer. As part of the process to demonstrate that it is qualified, the RU performs a subset of the original validation.
Typical parameters may include:
Revalidation may also be required in case of a method change. For example, the SU may use a different brand or model of instrument than the RU. In this case, revalidation may be required to demonstrate that the method is not only transferred, but that it is also validated on the new instrument 2.
In a limited number of cases, AMTs may be omitted. One example would be methodologies in which the presence of the sample does not impact the analytical technique and the RU already has documented experience on that technique (e.g., pH, loss on drying, melting point, etc.) A justification should always be prepared detailing the reasons why this approach is appropriate3.
7. Type of Training:
Proper training is another prerequisite for AMT success. Generally, three types of training methods are used during AMTs:
- Remote. This is the simplest and most commonly used training process. The RU trains solely based on the information provided in the transfer package. However, remote training is also the source of most preventable failures.
- Onsite. In this case, the SU trains the RU onsite (at either the SU or RU lab). This method is generally preferred for biotechnology companies and/or in case of complex AMTs. It is costlier and more time-consuming than remote training, but it generally leads to relatively few transfer issues.
- Dual onsite. This training process is the most complex and is typically used only for extremely complex methods.
It has a very low failure rate, but it is very time-consuming.
➢ The RU sends its analysts to train at the SU laboratory and to generate data with the SU.
➢ The RU analyst and the trainer from the SU then travel to the RU to generate data at the RU2.
8. Common issues need to avoid:
To avoid common pitfalls in the AMT process, it is important to recognize them:
➢ Unclear method instructions
These are at the root of most common issues. In this case, the RU interprets a method instruction differently than the SU. For example, a method may require the analyst to “prepare a 1-ppm solution,” but PPM can be defined as either gravimetric (μg/g) or volumetric (μg/mL).
➢ Method not written for external use
This issue should be caught during the initial evaluation stage, but many times it is not. An analytical method being transferred should not refer to or rely on any internal documentation or SOPs that are not provided to the RU.
➢ Impurity methods: Relative response factors (RRFs)
When transferring an impurity/degradant method that relies on RRFs, do not assume that RRFs will be the same between laboratories. Always verify the RRFs at the RU.
➢ Arbitrary acceptance criteria
Acceptance criteria must be meaningful and appropriate for the method and should be based on the method’s day-to-day performance. Setting arbitrary criteria can lead to faulty transfers—either in failing a transfer that should have passed from a practical, scientific standpoint based on the method’s historical performance or in passing a transfer that should have failed.
A commonly overlooked issue is bias in the obtained results. Bias refers to< a systematic difference or error of results between the RU and SU. For example, the acceptance criteria for an assay method transfer may require that the RU and the SU data agree within ±1% for triplicate analysis of three lots.
The RU data fall within this range, but all results of the RU are 0.8% lower than the SU. While this passes the acceptance criteria, it could still mean that there is a systematic difference or error (bias) associated with the RU data that could result in the RU failing release specifications for the material being tested that should have passed 2.