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34 BioPharm International eBook December 2019 www.biopharminternational.com remaining 400 items each year are assessed and filtered to find about 100 with minor 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 effectiveness of this deep-dive to determine the impact of proposed pharmacopoeia revisions; one group usually does not have all the necessary information. 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 important to understand that proposed changes must not be implemented, because they are not yet official. 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 official date for the pharmacopoeia revisions. This is shown in Figure 3, which represents a typical timeline for a proposed revision to become official. 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 product registrations, especially for those changes that have been identified to have major impact. The impact assessment for proposed pharmacopoeia updates enables effective planning for implementation if/when they become official. Most revisions proposed by the pharmacopoeia Proposal Published New Edition/ Supplement Published Comment Deadline Pharmacopoeia Activity Official Date 0 3 Total Time (months) 12 18 12 months to plan for implementation 6 months to implement Figure 3. Typical timeline for pharmacopoeia revisions to move from proposal to official. Regulatory Sourcebook Pharmacopoeia Compliance Series Bio/pharmaceutical industry surveillance of compendial changes: Process in detail (cont.)