Authors: Robert Beall (ProPharma Group), Penny Butterell (Pfizer), Kurtis Epp (CSL Behring), Lois Hintz (Corden Pharma), Russell Miller (Lilly), Rusty Morrison (Commissioning Agents), Mike Westerman (IPS)
The authors would like to thank Gretchen Allison (Pfizer), Joanne Barrick (Lilly), and Jennifer Walsh (BMS) for all of their hard work and support.
This paper discusses the nuances of lifecycle validation implementation at contract manufacturing organizations (CMOs).1 Much has already been written on the general implementation of best practices for lifecycle validation, including the elements of quality by design (QbD). [1–3] CMOs have unique considerations for lifecycle validation implementation, however. These include differentiating responsibility for various stages of lifecycle validation for both the CMO and the customer, implementing quality systems that allow flexibility for various customer approaches, process knowledge‐ transfer mechanisms between the CMO and the customer, and generating a quality agreement that captures the elements of lifecycle validation.
This paper discusses how CMOs can establish unique working partnerships to implement a process validation (PV) lifecycle approach for active pharmaceutical ingredient (API) and drug product production.
Life cycle stages discussed in this paper are:
Process design: The process is defined, based on knowledge gained through development and scale‐up. The sending site should plan knowledge transfer, the use of communication tools, and how cross‐ company teams will use and interpret process fitting. [4, 5]
Process qualification: The process design is evaluated to determine if it is capable of reproducible commercial manufacturing. This typically includes developing an approach to evaluate equipment selection and qualification, and agreeing on the approach to process validation and production of the initial PV lots. [6, 7]
Ongoing process verification: Confirms that the process remains in a state of control during routine production and post‐commercialization. [7, 8]
A confidentiality agreement should be in place prior to starting any project. It should be reviewed and accepted by all stakeholders.
The agreement should cover nondisclosure of partnerships that have not been made public. It should also detail how intellectual property (IP) will be used, what use of IP is prohibited, and whether IP will be applied to competitive products or used to generate competitive products. The agreement should also indicate if IP rights will extend beyond the related process or product.
IP may be related to:
The contract should also include quality assurance (QA) and commercial agreements. The cost of implementing the contract should be stated clearly.
A transfer agreement may be required to allow the MAH to share product information, ingredients, or other IP‐protected materials as part of the transfer. The agreement may include a non‐use provision. Before sharing any documents, team members should consult with legal.
A knowledge transfer is typically required to allow process design data from MAH development activities to be understood and adapted for the establishment of critical process parameters by the CMO. It should include detailed information on deliverables (including raw materials), development work (sometimes in a database), storage and transport, cleaning, analytical, and regulatory aspects. The details maybe loaded into a shared file, but the knowledge should be transferred in a way that is understood and confirmed by the personnel performing tasks.
One way to accomplish this is to detail the process in action‐based maps (flow charts) developed by the working and quality assurance teams. Maps should highlight product‐specific activities and give special attention to the rationale for changes. It is the MAH’s responsibility to ensure that information provided to the CMO is clear and concise. While coherent communication is always required for technical transfers, it is essential between the MAH and CMO, as the costs for failure increase significantly as the stages progress.
A process design plan should use a risk‐based method to define critical quality attributes derived from product and process knowledge, clinical trials, and other data. A production process should be based on design (e.g., QbD) data and any historical information available. The MAH and CMO should work together to provide developmental information, including goals of different lots that were produced, parameters that were adjusted, and effects on the process or product. Risk evaluation will also improve process understanding and help identify critical process parameters. The MAH should send retained samples of development batches to the CMO for evaluation and confirmation that both analytical and production results are comparable.
Development data should be managed adequately (preferably in a matrix database) and provide the basis for the technology transfer. Data should include information on raw material, processing, and analytical variants.
Assess analytical methods against current standards, regulatory standards, and their applicability to the product. If the matrix database contains significant data points from each batch, use look‐up tables to compare key data. A gap assessment to compare critical process parameters (CPPs) and critical quality attributes (CQAs) can help determine risk‐reduction methodology. Scale‐up may require additional strategies and proof that the process will meet the verification requirements.
When sending samples, in‐process materials, and finished products between sites, shipping condition testing should be conducted to determine the environmental and physical effects of shipping on the product. Shipping condition testing is especially important if the material will be stored, shipped, or distributed across different climatic zones or if seasonal changes may affect the product.
Providing a process design summary report and raw data tables to the CMO will facilitate the technology transfer. The report should include a defined manufacturing process, completed CPP/CQA matrix, completed risk evaluation, control strategy plan, risk‐reduction plan, test‐method variability, and statistical assessments of available pilot, engineering, and control data. Process variation to date should be identified and used as a predictor for validation readiness. Ideally, before proceeding to validation batches a process should demonstrate control, with critical process values falling within predefined limits and data indicating expected distribution.
When transferring production capabilities to another site, a skill set assessment can measure the training and knowledge of CMO personnel against the product requirements. High risk gaps should be addressed with a training plan; this may include having MAH personnel train CMO personnel.
Read more by downloading Implementing Lifecycle Validation Practices at Contract Manufacturing Organizations Discussion Paper.