Drug companies face growing pressures to accelerate the development and commercialization of novel medicines that are more effective and cost less than current treatments, while meeting increasing expectations for quality and safety. Contract manufacturers with demonstrated experience developing robust processes and successfully navigating the approval process for Fast Track, Breakthrough Therapy and other special designation products are in high demand. These service providers help their pharma partners meet both their aggressive deadlines and regulatory requirements by implementing an effective process qualification strategy.
In order to receive regulatory approval for commercial sale of a new drug, the manufacturer must demonstrate, through the collection of appropriate data, that its production process is highly robust and consistently provides the desired product (both API and drug product) within all specifications (purity, quality, potency, etc.). Successful process validation cannot be achieved unless manufacturers thoroughly understand their processes and the impact of process variations on product quality. Therefore, process validation is most effectively achieved when quality is designed into the product and process from the start.
Once Quality by Design (QbD) studies are completed, the effectiveness of the QbD studies is evaluated by doing a reconciliation of all the action items defined in the original Quality Risk Assessment (QRA) that was used to define the QbD studies. This reconciliation and/or a more formal Failure Mode and Effects Analysis (FMEA) are conducted to identify and resolve any gaps in process knowledge and to determine the level of risk presented by remaining potential process variations. The risks of significant impacts due to variation in different process parameters (rate of charging, reaction temperature, reaction time, etc.) are considered. If a high risk is identified, further studies are conducted to determine the level of variation that can be tolerated, and mitigation plans are designed to prevent unacceptable results.
Analytical readiness is also evaluated during QbD activities. Successful prioritization requires consideration of time sensitivity to meet aggressive timelines for accelerated programs (methods for the first step of a multi-step process), the extent of the required analysis (starting materials require fewer analyses than APIs) and the level of available knowledge and information (sponsor may have completed some to no method development work).
Any issues that may impact the ability to successfully complete process validation (i.e., those that represent high risk), must be addressed prior to process performance qualification (PPQ). Data collection and other activities that are required to resolve low-risk issues, such as generating reports, can be carried out concurrently with PPQ.
By this point, it is also highly preferable for the sponsor to have a clearly established regulatory strategy that identifies the specific countries in which applications for approval will be filed. Different countries have different filing requirements, such as for analytical method validation. The most efficient approach is to ensure that all the necessary work to meet the most stringent requirements is completed upfront.
Establishing regulatory starting materials (RSMs) and campaign strategies is also necessary prior to initiation of PPQ. FDA must approve the RSMs used at the beginning of cGMP manufacturing. In some cases, the agency may not notify the CDMO or sponsor company until the point of final approval. There is, consequently, a risk that the agency will require a different RSM strategy — and thus that cGMP manufacturing begin at an earlier step in a multi-step process. If there is any question regarding the approval of the RSMs, risk mitigation can be achieved by validating additional process steps. However, this decision must be made after carefully weighing the level of risk against the time and cost associated with validation of the additional step(s).
The campaign strategy will often depend on the needs of the sponsor. The general question is whether to validate and campaign each step individually or the entire process from start to finish. To minimize risk with a process or to provide material to meet clinical demands, it may be preferable to run through all of the steps once, in order to confirm that the product meets specifications, and then subsequently campaign the remaining batches for each step. Regardless, it is difficult to justify a successful validation/PPQ demonstration with less than three complete manufacturing runs.
Preparation for the process performance qualification stage involves close collaboration with the sponsor during all of the activities outlined above. Process History Tables (PHTs) are updated, and Critical Process Parameters (CPPs), Critical Quality Attributes (CQAs) and Critical In-Process Controls (CIPCs) are identified or updated. The CPPs are the parameters that most affect the process and product quality as determined by evaluating the results of Design of Experiments (DoEs) and other laboratory and pilot plant studies. Control of these parameters must be demonstrated during the PPQ. A PPQ checklist is generated and confirmed to ensure all necessary documentation is in place and any concerns/issues are discussed and resolved prior to manufacture of the PPQ batches.
PPQ must be performed under cGMP conditions, according to an established protocol. The written protocol must include details of the manufacturing process (including materials, CPPs, etc.), process controls, data to be evaluated, sampling and analytical methods, acceptance criteria for process performance, handling of deviations, equipment and facility/equipment design and qualification, operator training and analytical method validation.
In addition to demonstrating control of the process, the homogeneity of the product must also be established. The guidelines are somewhat vague on this issue; however, since they only apply specifically to the drug product, for which all doses must be equivalent, similar expectations do carry over to the API. For the latter, sampling and testing protocols become important because the API is not packaged in doses. Thus, it must be demonstrated that a small sample is truly representative of the entire batch — all samples, regardless of where they are collected, must be the same within some statistically significant limit. The team must decide which parameters to select for assessment and which criteria should be used to assess homogeneity. Meeting specifications may be sufficient, but typically the criteria and corresponding data are statistically set and verified.
For instance, if a solid API is dried in an oven using multiple trays, it is necessary to demonstrate that the material on tray one is identical to the material on tray two or three. In this case, homogeneity is demonstrated through extensive testing. Multiple samples are taken from each tray, and each sample is compared to all of the others. This approach is labor-intensive but is effective for demonstrating homogeneity. Alternatively, products dried in a filter dryer with continuous stirring, which are expected to produce a more homogeneous product, require much less extensive sampling and testing.
Cleaning validation also takes place during the PPQ, and the strategy for validation is dictated by the use of the equipment (shared vs. dedicated), and whether the PPQ process will be campaigned at each step or run from start to finish for each batch.
A strategic decision must also be made regarding when to file the new drug application (NDA): either when only the protocol has been developed or when the PPQ (i.e., validation) has been completed. Both approaches are allowed in the regulations. The first approach can accelerate the time to approval since the PPQ is completed after the NDA has been filed and during its review. However, there is risk involved, and unexpected complications in completing the PPQ may arise causing potential delays in the commercial launch. For traditional projects, according to the 1992 Prescription Drug User Fee Act (PDUFA), FDA has a goal to complete NDA reviews within 10 months. If there is confidence in the manufacturing process (e.g., a QbD approach was used during the initial development phase) and comprehensive pre-PPQ planning has been completed, then this strategy may be beneficial for speeding up the approval process. For accelerated projects, however, such an approach is not recommended, given that the goal for completing NDA reviews for these projects is just six months.
Completion of an accurate and comprehensive PPQ report with tabulated data and analysis results, as well as assessment of adherence to the PPQ protocol, is required. Unexpected results and any process deviations must be described and explained. Any necessary changes to the process and/or controls based on these results must also be clearly outlined. A statement indicating whether or not the data supports successful demonstration of process qualification is essential.
Ash Stevens has been executing QbD principles for the development of robust manufacturing processes for many years. The early adoption of a QbD approach has, in fact, contributed to the company’s extensive track record for commercialization of APIs and continues to facilitate accelerated approvals. The use of a practical qualification strategy also enables Ash Stevens to efficiently validate the processes it develops following QbD principles. With 14 manufacturing approvals in support of NDAs, Ash Stevens has repeatedly demonstrated that it has the ability to support the approval of many different types of APIs, with an effective strategy that facilitates smooth process validation. Appropriate preparation and planning ensures that all central issues are identified, and surprises during validation are minimized. Experience with the latest guidelines also means that Ash Stevens can address the issues of importance to the various regulatory agencies. All of this knowledge and experience is shared with clients on a regular basis. The most effective process performance qualifications are concluded when Ash Stevens and its clients form true partnerships and work closely as teams. Successful process validation sets the stage for the pre-approval inspection (PAI).
Vince Ammoscato currently serves as Vice President of Operations for Ash Stevens Inc. in Riverview, Michigan. With extensive experience in multi-step regio- and stereoselective synthesis, including synthesis of nucleosides, peptide-based compounds and heterocycles, Ammoscato has served as the prime technical contact between Ash Stevens and external clients. Ammoscato holds a B.Sc. chemistry, 1988, and a M.Sc. organic chemistry, 1990, from the University of Windsor, Canada.