By Susan J. Schniepp
Regardless of the phase of development and the level of GMPs being applied, there should be adequate controls and knowledge to assure patient safety, according to Susan Schniepp, fellow at Regulatory Compliance Associates.
Q. I work in the quality and regulatory departments of a contract manufacturer. We have clients with products in various stages of development that are using multiple contracts with multiple services providers for various stages of the manufacturing process. I always struggle with knowing which level of current good manufacturing practices (cGMPs) apply to different development stages. Can you provide some guidance on this point?
A. In today’s pharmaceutical environment, it is not uncommon for more than one company to be involved in the development of a product. Virtual companies may use the services of a contract laboratory, a contract manufacturer, a contract research organization (CRO), etc., to develop their products from conception to market approval. Some of these relationships can be complex, so it is important for every organization involved in the drug development process to be familiar with what the applicable GMPs are and at which stage of the development process they apply (1-4).
Areas to be reviewed to determine the appropriate level of control needed in concert with the phase development stage include: level of validation of test methods, level of detail needed in batch records, level of control needed on incoming materials, and facility and equipment controls. An example is qualifying raw materials. In Phase I/II of the development process, you may only decide to document the source and quality of the material used to produce the product; when you enter into Phase III you will want to qualify your supplier and establish a quality agreement in addition to the material qualification.
Although not all GMP requirements apply to products in the early stages of development, the requirements for change control and deviation investigation should be robust and utilized at all stages of product development. The information documented in change control and as part of an investigation helps ensure that process improvements are efficient and do not repeat strategies that were discounted during earlier stages in the development process. It also helps to capture the product and process history needed in the later phases of development for the process validation activities.
To determine the impact of the deviation on the product quality, it is important to determine the ‘root cause’ of the deviation. The process used in the industry to determine root cause is, of course, the investigation procedure. This procedure, regardless of whether the product you are investigating is biotech or traditional, or new or old, should require the investigator to review various systems and determine whether they were the cause of the deviation being investigated. This concept is important because of the aforementioned possibility that more than one company is involved in the product development. When more than one company is involved, there is a necessity for technology transfer (5,6). Without a robust and transparent exchange of information, the technology-transfer activity has the potential to be frustrating and delayed while people try to find a common understanding and locate necessary information crucial to the success of the drug development process. It is important to keep in mind that change control and deviations are critical elements for ensuring product quality and patient safety regardless of the stage of development a product is at in the product lifecycle.
The criticality of an efficient change-control system that can track and ensure proper evaluation and implementation of changes should be obvious at all stages of product development. As a change becomes more complex (e.g., a change that involves multiple products and country registrations), it becomes harder to implement. Complex changes are difficult enough for a single company with multiple sites, but they are even more exaggerated for virtual companies. For the latter, multiple contract service providers are often involved and each one has its own processes and procedures for managing a requested change.
The time required to transfer, validate, train, and obtain regulatory approval for multiple products requires enormous coordination. It is important to keep in mind that as the complexity of the change increases, the need for additional resources can also increase. The complexity of the change can impact the strategies for implementation, the tactics needed to effectively implement the change, and the time it takes for a change to be approved. At the same time, drug license holders will need to establish consistency in their regulatory filings without affecting product quality. When dealing with this change, focus on the steps needed to effectively implement the change. Working closely with your CMO/CRO to identify an accurate timeline for completion, including the necessary training required for employees, can help expedite the time it takes to complete the change request. Coordinating these activities with regulatory requirements also will help ensure necessary changes are implemented globally in an efficient and effective manner throughout the product lifecycle.
Applying the correct level of cGMPs to the product development stage is really a matter of common sense. The earlier the product phase is, the more flexible your requirements. As the product approaches Phase III, the board requirements should mimic commercialization requirements. The concept is the GMPs applied should be appropriate to the stage of development and that ‘full GMPs’ should be in place during the later stages of clinical development where the final safety and efficacy of a product are being established. Keep in mind that regardless of the phase of development and the level of GMPs being applied, the first and foremost thought when releasing product at any stage for human consumption is: are there adequate controls and knowledge to assure patient safety?
References
1. FDA, INDs for Phase 1 Studies of Drugs & Biotech Products [2], November 1995.
2. FDA, Draft Guidance: INDs-Approaches to Complying with CGMP’s for Phase 1 Drugs (CDER, CBER, Jan. 6, 2012)
3. FDA, INDs for Phase 2 and Phase 3 Studies: Chemistry, Manufacturing and Controls Information [3](May 2003).
4. European Commission, EU GMPs, EudraLex, Volume 4 Annex 13 [4].
5. EC, EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use.
6. FDA, Guidance for Industry, Contract Manufacturing Arrangements for Drugs: Quality Agreements (CDER, CBER, CVM, May 2013).
