PQRI / FDA Workshop
Manufacturing Science encompasses knowledge about products and processes, technology used to manufacture and control these processes, and the underlying foundation of a robust quality system at the manufacturing site.
The Desired State:
The desired state is based on a sharing of knowledge. The knowledge base begins in research and development and continues though technology transfer and commercial manufacturing. Information related to the active pharmaceutical ingredient and drug product formulation, manufacturing processes and analytical methods, critical to quality parameters/attributes, and product specifications are all key elements of the knowledge base.
Currently, firms have a substantial knowledge base on products, however, due to traditional regulatory expectations, only the knowledge requested by FDA is shared. This knowledge base varies from product to product and from firm to firm, but is constantly increasing. FDA may not currently understand what knowledge is available or what the Agency needs to understand the capability of pharmaceutical processes and the key fitness for use indicators.
Firms use the knowledge to understand process capability and the risk of an event impacting fitness for use. Continuous improvement efforts are employed to increase process capability and reduce risk. Risk mitigation strategies using innovative technologies are limited due to real and perceived barriers to implementation.
One of the barriers is the existing regulatory process that does not facilitate the sharing of knowledge and hinders the ability of industry to fully leverage improvements in manufacturing science. Since the knowledge base and potential risk mitigation strategies are not shared, regulatory processes remain inflexible and disproportional to risk in some cases. One area where certain FDA District Offices currently demonstrate limited flexibility is in exercising the option to waive PAI inspections for facilities with good compliance records.
Manufacturing science is dynamic. To achieve the desired state, the regulatory processes have to be similarly dynamic. Four key elements are needed to move from the current state to the desired state.
1. Knowledge sharing – what, how and how much?
2. Risk classification using appropriate methodology.
3. Risk mitigation where feasible using technology.
4. Regulatory processes proportional to risk.
The knowledge sharing process (action item #1) by the firm should be sufficient to provide FDA with an understanding of the following:
· Formulation is appropriately justified .
· Critical to quality parameters and attributes are known.
· Preliminary process capability data is available.
· Rationale for specifications and analytical methods.
With this knowledge the firm and FDA can determine the potential for events to impact fitness for use (i.e. risk). Using a mutually developed risk classification system (action item #2) a product can be classified.
A firm may choose to mitigate risk using advanced technologies (action item #3). By sharing risk mitigation strategies with FDA the product may be reclassified to a lower risk class. This is one of the key benefits of a science and risk based approach to GMPs.
PAT is an example of an advanced technology that can both facilitate building the knowledge base and mitigate risk. PAT will allow a better understanding of changes that impact fitness for use thereby reducing the risk implementing process change. PAT is not a panacea, cannot be applied everywhere, and should not be considered mandatory. PAT will change the traditional concepts of process validation and lead to continuous quality verification strategies.
The preceding items are prerequisites to establishing science and risk-based regulatory processes. Such processes will ensure FDA resources are focused on the highest risk areas and firms are encouraged to use innovative technology to mitigate risk. However, it is incumbent upon the firms to ensure that low and medium risk areas remain in appropriate state of control, since these risk classes will receive less regulatory attention. The regulatory processes will remain unchanged from today when a firm chooses not to use technology to mitigate risk.
Examples of science and risk based regulatory processes follow:
i. Use industry/association personnel to provide training
ii. Bring training in-house to FDA to reach more people
iii. Leverage FDA’s internal experts
iv. Provide learning sabbaticals in industry
i. Desired alternative is to have quality systems inspections determine if a facility is acceptable from a cGMP perspective and only selectively use PAIs for inspecting new technology, previously non-compliant firms, first-in-class products, high risk products etc.
i. Information is learned about a process during the first year of commercial production that could only come from manufacture in a routine environment. This information is critical to providing better control of the process and quality of the resulting product.
ii. There is a reluctance to submit multiple changes/improvements because the regulatory process does not provide this level of flexibility without significant studies or justification
iii. The result is that industry usually opts to forego many of the improvements
iv. The desired flexibility would be to allow multiple changes/improvements in a single supplement
i. Expansion of SUPAC guidance
ii. Consider development of a PAT SUPAC (developed similarly to the equipment SUPAC)
i. Evaluate and redefine, as needed, the use of prior approval supplements, changes being affected supplements and annual reports.