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34 Pharmaceutical Technology REGULATORY SOURCEBOOK DECEMBER 2019 P h a r mTe c h . c o m Pharmacopoeia Compliance Series impact, and the remaining 300 items with no impact. A simple example of a proposal with no impact is a change to a detail in an analytical procedure, when it is found on further assessment that the specific detail is not listed in testing standards or product registrations for the company. Another example is a change proposed by USP to the monograph for a pharmaceutical ingredient, when it is found upon assessment by the manufacturing site that the associated product is only marketed in Europe. It is helpful to also have confirmation from the regulatory group that USP requirements are not listed in the product registrations for that ingredient. It is worth noting that input from multiple functional areas across the company helps to increase the ef fectiveness of this deep-dive to determine the impac t of proposed pharmacopoeia revisions; one group usually does not have all the necessary information. A change control process is challenging at best, but is a critical part of the compendial process to ensure compliance with current pharmacopoeia requirements. What has been achieved by the process at this stage? A company has been able to take a total of 3000 changes published per year by the global pharmacopoeias, and through a series of filters and further assessment, determine that only about 200 of these truly have impact. The effort needed to identify the revisions with impact is neither quick nor easy, but it is beneficial as it enables the company to then focus on the 100 major changes and the 100 minor changes to determine next steps to maintain ongoing compliance. For major changes, which typically have broad impact across the company, the impact assessment benefits from a "targeted compliance team," ensuring input from all potentially impacted areas regarding the specific, targeted pharmacopoeial revision. This team is comprised of representatives from appropriate functional areas, including the supply-chain function and impacted manufacturing/ stability sites, since no single group can identify the impact of a major change to every area in a company. The targeted compliance team has the responsibility to provide input on the proposed change to help in the development of a possible response to the pharmacopoeia, and equally important, to develop the company's implementation plan for the specific compendial update being evaluated. Any lab work and data mining performed to support the company's response to the pharmacopoeia is also valuable in the second action at this stage—determining the implementation plan for the proposed change. Each proposed revision with major impact to the company will affect different stakeholders to different degrees, and it may be questioned who has the decision rights for such a team. The answer is that decisions about the implementation plan must be made in the best interest of the company overall, with input from each area weighed in the determination, and the ultimate benefit to patients firmly in mind. For minor changes, a cross-functional team may not be required to develop the implementation plan, but a similar decision process can be used to determine how best to proceed. It is impor tant to understand that proposed changes must not be implemented, because they are not yet of f icial. Though it may seem premature to begin planning for implementation at this stage, doing so increases the likelihood that the changes can be put in place by a company in the relatively short time between the subsequent publication and designated of f icial date for the pharmacopoeia revisions. This is shown in Figure 3, which represents a typical timeline for a proposed revision to become of ficial. Time zero is set as the publication of the proposal, with three months allowed by the pharmacopoeia for public review and comment. Once the comment deadline ends, the pharmacopoeia organization continues their process, leading to publication of the official change in a new edition or supplement. The minimum time taken by the pharmacopoeia to accomplish this is about nine months, although it often takes longer. Once the update is published in the new edition or supplement, six months is usually allowed for its implementation. Starting to develop the implementation plan at the proposal stage provides a minimum of 18 months to accomplish this important work and help maintain ongoing compliance, a full year longer than the six months available after the updates are published in the new edition or supplement. This extra time can be invaluable in making the necessary updates to a company's procedures, documentation, and produc t registrations, especially for those changes that have been identified to have major impact. The impact assessment for proposed pharmacopoeia updates enables ef fective planning for implementation if/when they become of ficial. Most revisions proposed by the pharmacopoeia move forward from proposal to official without significant change from what was initially proposed. In the authors' experience, 90% or more of proposed changes move forward 90% of the time with no major change to the proposal. If there are significant changes, as sometimes seen with proposals for new or significantly updated general chapters, the pharmacopoeia will typically publish another draft for review and comment before becoming official. Given this situation, the sooner a company can assess the impact of a pharmacopoeia revision (i.e., at the proposal stage), the better they are able to plan for a smooth implementation of the change, especially given the challenges associated with official change control processes in many companies. This evaluation also enables the submission of comments to the pharmacopoeia, when necessary, advocating in regard to changes that may be unacceptable or unachievable for the company. Official changes: Evaluate and proceed with implementation. The pharmacopoeia process to introduce new and revised monographs and general chapters continues from the proposal stage to the subsequent publication of updated requirements that become official through new editions and supplements. The publication of these updated requirements triggers the f inal phase of the industr y sur veillance process. The specific steps performed by a company at this official stage are essentially the same as described for the proposal stage: monitor the publications, filter for impact, communicate, and evaluate the changes. The ultimate goal, however, shifts to focus on implementation. If the Bio/pharmaceutical industry surveillance of compendial changes: Process in detail (cont.)