The 4th PDA Europe Annual Meeting will open with an overview of some of the latest regulatory developments.

Former UK MHRA regulator Andrew Hopkins and Irish Health Products Regulatory Agency representative Anne Hayes will offer their insights. Hayes will focus her talk primarily on PIC/S. Additional speakers from EMA and WHO have been invited.

During the first set of breakout sessions, one session will explore how to manage regulatory requirements.

The Quality Systems Interest Group will convene one day prior the meeting on June24. Big data will serve as the keynote presentation for this interest group meeting.

Other presentations during the interest group meeting will cover quality management systems (QMS), integrating quality risk management (QRM) into a QMS and best practices for conducting management reviews. Group discussions will be led, focusing on management reviews, metrics, QRM, knowledge management and more! Interest group leader Lothar Hartmann, PhD, Managing Director, PhACT GmbH, will moderate the presentations and facilitate discussion.

Quality systems are a key element of any pharmaceutical operation. In light of significant recalls due to manufacturing issues, quality systems are more critical now than ever. Fortunately, PDA members have a resource to expand knowledge in this area: The Quality Systems Interest Group.

The Quality Systems Interest Group offers a forum for discussions on current topics and coverage of developments related to quality systems based off ICH Q10: Pharmaceutical Quality System.

The group’s intention is to exchange information on the topic, share best practices, offer open discussion and develop practical approaches.

The group has grown tremendously since it was founded not that long ago. Currently, the group consists of the following 11 subgroups: management review, key performance indicators/metrics, continuous process verification, process owner, quality risk management, comparability of ICH Q10 with ISO standards, quality management systems auditing, quality manuals, knowledge management, training and documentation control.

For more information, please contact the chair of the group directly.

With only a few weeks of planning, PDA’s Quality Systems Interest Group pulled off a successful session on quality metrics Sept. 24 at the 2018 PDA/FDA Joint Regulatory Conference.

Despite having been listed on the conference agenda for a mere three weeks, the room was packed. Attendees came to listen to Steven Mendivil, Senior Advisor, International Quality External Affairs, and leader of PDA’s quality metrics task force, share a dialogue on quality metrics with Tara Gooen Bizjak, Senior Science Policy Advisor, Pharmaceutical Quality, CDER, U.S. FDA.

Below is a sampling of the discussion:

Mendivil: This is the first time that I have seen a second, and possibly even, a third draft guidance. Can you speak to some of the challenges FDA has experienced in this journey?

Bizjak: This has been quite a big effort—almost unprecedented in my experience… everybody has their own opinion, right? Just like in FDA. And just like with stakeholders in either industry or academia as well. So, I think there have been challenges but there are also opportunities. This is a really large opportunity for the pharma industry to really take that next step forward encouraging more modern quality systems and more modern manufacturing as well as an opportunity for FDA to learn from some of that information and be able to really make a…change in our regulatory oversight.

Right First Time

Mendivil: I think when it came to the points about a “common definition,” there was a sense that these might not be the most valuable metrics such as “right first time” metrics, which sounds conceptually great, but there is no common definition of what it is.

Bizjak: In fact, in the first Federal Register, notice we did not include right first time because of so many variable definitions for the concept of right first time and this internal evaluation process…we asked if right first time was a valuable metric to include and we did not receive a lot of feedback about that.

Recent Activity

Mendivil: Can you explain more about the two Federal Register notices that were published over the summer? One detailed how companies could arrange in-person meetings at FDA headquarters and the other covered how companies can request an FDA site visit.

Bizjak: There are two Federal Register notices. One is what we refer to as the feedback program and the other is the site visit program. The site visit program is fairly straightforward because everyone here is used to site visits—the concept of having FDA come out and visit the site, not issue a warning letter, not issue a 483, just to learn about the site. That is a more tangible process. It would be a one-time visit.

And, then, the second one is more of an in-depth opportunity to provide feedback and back-and-forth dialogue. We set this up using the meetings approach, like the Type C meetings and pre-IND meetings, as a mechanism to be able to have this dialogue. A company would provide information about metrics they feel are appropriate, definitions that work for them that they want to share with us and have that back-and-forth communication where a company could present, “This is what we do. This is how we run our quality metrics program, how we have adapted over time.” That sort of thing… they [the meetings] can be done virtually, too. This just has an opportunity for follow-up and more discussion.

Audience Question: Are both of these open to anyone?

Bizjak: That is correct. All the mechanisms are open to anyone who is applicable… it is open to everyone [barring Agency prioritization needs for site visits].

Excipients serve a critical role in the production of final dosage forms for drug products and biologics as they help the product fulfill its purpose (1). Recognizing this critical role, recent EU regulations require manufacturers to ensure appropriate levels of GMP for excipients through application of formalized risk assessments (2,3). As of March 21, 2016, excipient users/drug manufacturers in the European Union are legally mandated to perform needed assessments of excipient use/function throughout the entire supply chain.

A task force comprising representatives from both PDA and the International Pharmaceutical Excipients Council (IPEC) recently held a face-to-face meeting in Berlin to discuss developing a PDA technical report on the topic. Some U.S. colleagues even took time out of their evenings to phone in via Web conferencing.

In this meeting, representatives from pharma companies presented models for global solutions to introduce risk assessments for all excipients (oral, parenteral, inhalation, etc.). These examples will serve as generic risk assessment models within the planned technical report. The meeting also covered other hot topics, such as lifecycle management, complicated supply chains and benefits of the risk assessment. A supply chain matrix will be included within the technical report that outlines the different responsibilities of all parties within the supply chain, including brokers and contract manufacturing organizations.

The task force has completed a draft of the technical report’s overall framework. Now, the group has split into subgroups to work on detailed sections and key topics, such as risk mitigation. Currently, the task force hopes to have the technical report published sometime in Q1 of 2019.

Both PDA and the IPEC Federation believe that it is crucial to present “one voice” concerning the legal, regulatory and related issues around excipients, so this joint initiative will deliver one technical document that addresses the complex challenges of implementing risk assessments in this context. The IPEC Federation sees a great benefit in this collaboration, bringing in IPEC’s excipient expertise from one side and the drug product manufacturer’s perspective through PDA.

References

1. Holtz, F. “Formalizing a Risk Assessment for Excipients.” PDA Letter 53 (Jan 2017) 40–43.
2. European Commission. "Directive 2011/62/EU.” Off J Eur Union L 174 (2011): 74-87.
3. European Commission. “Annex 1: Manufacture of Sterile Medicinal Products, EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use.” Nov. 25, 2008.

The following is a summary of a study published in the September/October issue of the PDA Journal of Pharmaceutical Science and Technology.

After many discussions within various facets of the pharmaceutical industry over the last three years, it became apparent that quality culture is increasingly considered a competitive advantage by operational excellence (OPEX) and quality executives. Recent research indicates the positive impact of quality culture on a broad range of performance indicators, especially on the success of quality improvement programs. Currently, however, a shared understanding of quality culture, as well as practical and accepted metrics for assessing quality culture, is lacking.

In 2014, PDA conducted a survey on quality culture in the pharmaceutical industry. Based on this data, quality culture was assessed in a later survey by distinguishing quality system maturity from quality culture behavior (1). The former focuses on objective characteristics of a quality system that can be verified upon inspection. In contrast, the latter aims to assess employee behavior at the site/organization associated with a strong quality culture, such as open communication and engagement. The later survey looked at whether there is a positive relationship between quality system maturity and quality culture behavior. If so, assessing the maturity of a quality system might serve as a surrogate indicator for quality culture behavior, which is comparably difficult to assess with reasonable effort. Statistical regression line analysis between composed quality system maturity and quality culture behavior scores revealed a positive correlation, thus supporting quality system maturity as a proxy of quality culture behavior.

Since 2016, the Institute of Technology Management at the University of St. Gallen, Switzerland, has been conducting a long-term research project on quality metrics, financed by the U.S. FDA. In the course of the project, the team integrated quality culture into the research scope. For operationalizing quality culture as a precondition for statistical analysis, the St. Gallen team adopted a two-sided perspective on quality culture (1). The quantitative research is based on the comprehensive St. Gallen OPEX database, consisting of more than 350 pharmaceutical production sites. The database consists of a broad range of performance metrics, along with so-called enablers, from several pharmaceutical companies worldwide.

The paper “The Impact of Quality Culture on Operational Performance – An Empirical Study from the Pharmaceutical Industry,” available in the September/October PDA Journal of Pharmaceutical Science and Technology, summarizes the essential findings of this quality culture research. First, the research team retested the relationship between quality system maturity and quality culture behavior documented in 2015. This required the research team to operationalize both categories by matching the enabler from the OPEX database to the PDA definition. A regression analysis documents a strong positive correlation between both categories, substantiating prior findings. Second, the paper links the discussion of quality culture to performance outcomes. The team formulated the hypothesis that sites with a high capability of delivering high-quality drugs in the right amount and at the right time also demonstrate a significantly higher level of quality culture. A t-test analysis supports this assumption. Sites with high performance regarding quality and delivery reveal a significantly (p-value =.05) higher level of quality culture compared to sites with low performance.

The paper contributes to the ongoing discussion on quality culture. It confirms a positive correlation between improvements of the quality system maturity and the actual quality behavior of the employees. Further research might focus on identifying those elements of the quality system that have a comparably strong impact on quality behavior. In addition , the paper links quality culture, which is considered an enabler, to performance outcomes. The analysis indicates that investments in quality culture, including both the quality system and quality behavior, is positively associated with long-term benefits in terms of the ability to deliver high-quality products without the risk of shortages.

[Editor’s Note: The PDA Education course, “Quality Culture Assessment Tool and Training,” will be offered throughout November in Singapore, Taiwan and Santa Monica, Calif. For more information, visit the PDA website.]

Reference

1. Patel, Pritesh, et al. “Quality Culture Survey Report.” PDA Journal of Pharmaceutical Science and Technology 69 (2015): 631–642.

In addition to evening interest group meetings, some interest groups will convene during the lunch break at this year’s 2018 PDA/FDA Joint Regulatory Conference. Below is a schedule of meetings for regulatory-focused interest groups.

Monday, Sept. 24

12:30 p.m.–1:30 p.m.

• Pharmacopoeial Interest Group
• Regulatory Affairs Interest Group
• Supply Chain Interest Group

5:45 p.m.–6:45 p.m.

• Quality Risk Management Interest Group (joint meeting with Environmental Monitoring/Microbiology Interest Group)
• Management of Outsourced Operations Interest Group

Tuesday, Sept. 25

12:30 p.m.–1:30 p.m.

• GMP Links to Pharmacovigilance Interest Group
• Inspection Trends Interest Group

5:45 p.m.–6:45 p.m.

• Data Integrity Interest Group
• Quality Systems Interest Group
• Technology Transfer Interest Group

Since the release of the EU Annex 1 revision at the end of 2017, the pharma industry has been abuzz about its implications for the global pharma community.

On June 26 at 11:30 a.m., Session 1 of the 3rd PDA Europe Annual Meeting will include three talks addressing topics related to Annex 1. An EMA speaker has been invited to discuss the revision and a representative from the PDA Commenting Team will provide an overview of the team’s comments on the revision. The third speaker will review activities around pre-use/post-sterilization integrity testing (PUPSIT)—a key part of the Annex 1 revision.

Quality remains a popular topic for PDA members. PDA’s Quality Systems Interest Group will convene one day before the 3rd PDAEurope Annual Meeting, June 25, in Berlin. This all-day interest group meeting will explore current issues impacting quality systems. Register Now.

You do not need to be a member of the interest group to attend this meeting.

PDA recently completed a thorough review of the revision of EU GMP Annex 1, Manufacture of Sterile Medicinal Products, which was released for public comment on Dec. 20, 2017. The Annex 1 revision represents an important restatement of the EU regulatory position on sterile product manufacturing, both for aseptic processing and terminal sterilization. As the PDA commenting team prepared their comments, it became apparent that challenging questions remain for regulators and our industry. These questions are not limited to those posed by the Annex 1 revision; they are symptomatic of an industry struggling to meet the challenges of modernization and globalization. In short, challenges every technology-driven industry faces.

These questions include the following. What is the industry’s understanding around true risk- and science-based decision-making when it comes to aseptic processing? How can a balance be achieved between increased monitoring and reliance on robust sterility assurance design, such as when additional tests may increase risk to product quality? What are the limits of traditional testing methods? And what does the industry need in order to facilitate adoption of new technologies to manufacture and control product?

If these questions make you feel uncomfortable, they should. Because much of the way we think about them may be changing. And as they say, facing and addressing change should be a bit uncomfortable.

To help the industry and our members answer these questions, PDA is hosting a timely Sterile Medicinal Products Manufacturing Conference in Bethesda, Md., May 14–15. The conference planning committee, comprised of experts from industry and regulatory agencies, designed this event to bring together the sterile products community to discuss contemporary approaches for sterile product manufacturing through case studies and personal experiences. A special focus of the conference will be a review of the proposed Annex 1 revision and recommendations from the commenting team. The conference will also cover the following sterile product manufacturing and control essentials, among others:

• Updates on relevant PDA technical reports, USP chapters and global regulatory trends
• Sterilization and terminal sterilization challenges
• Environmental, personnel and product contamination control strategies
• Isolators and barrier systems
• Filter and container integrity testing
• Quality systems and quality risk management

Change is becoming ever more necessary, influenced by the expansion of global manufacturing, the availability of knowledge, the discovery of promising therapies and the availability of new technologies.

We as an industry must ask these difficult questions and explore new ways to address them to ensure the improvements that will be required in the 21st century. We recognize that it is time for the industry to face the challenges with the objective of implementing certain and effective process improvement.

If you are responsible for decision-making, design, validation, control, operation, maintenance or management of sterile medicinal product manufacturing, or if you influence those who are, understanding the discussions, regulatory expectations, challenges and ways to meet these challenges today is essential. For more information about the conference, click here.

In addition to this conference, PDA Europe will also host three one-day meetings in Spain, Ireland and Germany to cover the impact of Annex 1. The first meeting will be held May 17 in Dublin. To register, visit the meeting website.

Recently, I had the pleasure of providing an update on Chinese regulatory trends to PDA’s Regulatory Affairs and Quality Advisory Board (RAQAB). In general, while there are many new regulations coming from the China FDA, it appears Chinese regulators are striving to make sure their regulations are more aligned with international practices.

This reflects statements made by CFDA Director Bi Jingquan on Oct. 10 following release of the document, Opinions on Deeping the Review and Approval System Reform and Encouraging the Drug and Medical Device Innovation. In his remarks, he pointed to the need to expand China’s development of innovative drug products as well as increase importation of new drugs from abroad for serious diseases, noting that, from 2001 to 2016, the U.S. FDA approved 433 new drugs, yet only 133 of them have been marketed in China. At the same time, safety and quality of drug products should be ensured.

Below are the highlights I shared with RAQAB:

• All post-approval changes (PAC) must be submitted online as of Dec. 1, 2017; these will be reviewed centrally by CFDA’s Center of Drug Evaluation (CDE) as provincial CFDA offices will no longer accept nor review PAC submissions
• The Market Authorization Holder program will be implemented in China in the future (right now, only ten provinces/cities are allowed to participate the MAH pilot program); this change could have a dramatic impact on the Chinese pharmaceutical industry, for example, the term “imported drug” will now refer to drugs manufactured outside China but marketed in China, which may mean reduced testing at customs (some provinces have already dropped the testing fee for imported drugs in China)
• APIs will be reviewed in conjunction with NDA and ANDA applications, and there will no longer be a separate CDE review of API applications; API manufacturers are encouraged to file Drug Master Files with the CFDA, and there will be no “pharmaceutical production license” issued to API manufacturers in China
• The “GMP Certificate” issued by CFDA will cease; the intent is that preapproval inspections (PAI) will cover general GMP inspections as well
• The five-year GMP recertification for onsite inspections will be converted to routine onsite GMP inspections based on a risk model being developed by CFDA
• A revision to the Drug Administration Law is expected to be passed in the next Chinese Congress sometime in Q1 2018 so as to enable the above changes
• A new piece of Chinese regulation pertaining to “Drug Data Governance” has been published for comment—this is the third version published for commenting (PDA commented on the first version of the regulation), and the contents are now more aligned with current international guidelines regarding data integrity; this regulation is intended to govern data integrity and reliability in the whole lifecycle of pharmaceutical products in China, covering GxP, not only GMP

Anyone interested in learning more about Chinese regulations is encouraged to contact Denyse Baker.

The 2018 PDA Annual Meeting features a new format for interest groups; instead of convening after the last session of the first two days, interest groups will convene at the same time as breakout sessions. Below is the schedule for the regulatory-focused interest group on the schedule at the 2018 PDA Annual Meeting.

Tuesday, March 20

1:45–3:15 p.m.

The Quality Risk Management Interest Group

For more information about interest group meetings, visit the Annual Meeting website.

The European Commission published the long-awaited draft of Annex 1 “Manufacture of Sterile Medicinal Products” in December 2017. PDA is currently working with a team of 15 volunteers to comment on this document.

Hal Baseman, Chief Operations Officer, ValSource, and Gabriele Gori, Vice President Audit and Risk Management – Global Quality, GSK Vaccines, are leading this team. Both also served as co-chairs for five workshops on Annex 1 PDA sponsored in the United States and Europe in 2016 and 2017. Jahanvi (Janie) Miller can be contacted for any further details. A session at the 2018 PDA Sterile Medicinal Products Manufacturing Conference will review PDA’s comments. Register to attend.

Excipients serve a critical role in the production of final dosage forms for drug products and biologics as they help the product fulfil its purpose (1). Recognizing this critical role, recent EU regulations require manufacturers to ensure appropriate levels of GMP for excipients by using formalized risk assessments (2,3). As of March 21, 2016, excipient users/drug product manufacturers in the European Union are legally mandated to have performed the needed assessments of excipient use and function throughout the entire supply chain.

In 2016, following an initial webinar, a team under the PDA Quality Risk Management Interest Group exchanged their experiences on meeting this requirement. The group then surveyed other companies, finding that these companies have comparable questions. Different solutions have been found in different companies, but similar principles apply.

The group has joined forces with IPEC, who in 2016 published a guide for excipient users on the subject (4). Now, this group and IPEC will work together to produce a joint technical report. The group will form subteams for different specific topics. Volunteers working within these subgroups will consist of representatives from both PDA and IPEC, and reflect manufacturers and suppliers. Volunteers interested in sharing their company experience and working on the TR are welcome to join the group. Please contact PDA’s Volunteer Coordinator.

The technical report will provide examples of industry practices, and propose a generic solution. The document will serve as practical guidance intended for use along with existing regulatory and industry standards. The technical report team expects that the document will enable manufacturers and CMOs to either set up or benchmark their systems, and further establish collaboration with excipient suppliers and distributors.

References

1. Holtz, F. “Establishing a Formalized Risk Assessment for Excipients.” PDA Letter (January 2017) 53: 40–43.
2. “Directive 2011/62/EU.” Official Journal of the European Union 54 (2011): 74-87.
3. Guidelines of 19 March 2015 on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use (2015/C 95/02)
4. March 18 2016, IPEC Europe “How to” document related to Guidelines of 19 March 2015 on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use (OJ 2015/C 95/02)

How has PDA’s Elements of a Code of Conduct for Data Integrity in the Pharmaceutical Industry impacted the companies of those who downloaded it?

The Code is a collection of recommended best practices for employee and management conduct related to data integrity, presented in a ready-to-use format. It was published on the PDA website in March 2016, available free for download. PDA’s Data Integrity Task Force, under the leadership of Anil Sawant, PhD, Vice President, Quality Management Systems and External Affairs, MSD, and Ronald Tetzlaff, Corporate Vice President, PAREXEL, developed the Code with the goal of sharing it with the industry at large. It was written to apply to employees, corporate officers, third-party suppliers and others acting on behalf of, or at the behest of, a company. This includes individuals that develop, test, manufacture or submit marketing authorizations for pharmaceutical and biological products. The Code was designed so that it could be tailored for each individual company’s needs. A company could implement the elements within the Code in their entirety or only certain elements identified as pertinent for establishing their own customized policies, standards, procedures, or other quality system elements to define data integrity requirements.

The task force aimed to distribute the Code of Conduct as broadly as possible, thinking it would be especially useful for smaller manufacturing firms, or those that supply raw materials, components or testing services who may not yet have taken this step toward quality system and culture maturity. It was developed to be used directly by smaller firms to shore up existing quality systems. Additionally, larger firms or contract givers could use elements of the Code to assess their current internal codes or use it to when drafting or revising supply and quality agreements. As of October 2017, more than 3800 copies of the Code have been downloaded. Most of the copies were downloaded in North America, Western Europe and Japan, which is consistent with PDA’s large membership in these regions. Analysis of website data shows the downloads have also occurred in regions representing areas of emerging pharmaceutical manufacturing as Africa, Eastern Europe, India and China (Figure 1). This is encouraging as it supports one of the task force’s goals of expanding education and tools to identify and rectify data integrity gaps.

Figure 1 Number of Downloads by Region Outside of United States, Western Europe and Japan

One year after publication, PDA sent a follow-up survey to those who had downloaded the document to learn about the outcomes of implementing the Code, collecting a total of 95 anonymous responses. Approximately 40% self-identified as a quality leader or member of quality staff and 20% as compliance leaders or compliance staff. Another 30% identified themselves as consultants. The remainder self-identified as members of manufacturing production, legal counsel, validation, development and marketing.

There was an almost even distribution in the size of the respondents’ companies as shown in Figure 2.

Figure 2 What is the Number of Employees in Your Company/Average in your Client’s Company?

Responses to the question regarding the location of manufacturing sites indicated survey respondents represent manufacturing sites from all regions of the world (Figure 3).

Figure 3 Where Does Your Company (or Client) Manufacture Products?

The survey also asked how the Code was used after being downloaded. More than half indicated they used the Code as a guide on good data integrity practices, while 33% used it as a benchmark to evaluate internal practices and 14% used the Code in developing agreements with outsourcing partners or suppliers. Almost 20% of the respondents adopted the Code in whole or in part into their internal business processes and practice. More than 90% of the survey respondents rated the Code as useful. A quarter also found it practical for their company or clients to adopt or follow.

More than 90% of respondents also indicated they believe it will help reinforce a culture of quality and trust within the pharmaceutical industry. This aligns with the original goal of the task force to raise awareness and provide useful tools within the pharmaceutical industry.

The survey included a question for openended responses. Here are some of the positive comments received about the Code:

• “I believe that your take on data integrity was accurate, because it is basically awareness of existing regulations. What I fear (and what you have thankfully not done) is over-engineering what regulatory agencies have already expected…similar to what happened with the term ‘risk-based.’ I applaud your paper because it was fundamental and basically summarized what was already expected in regs and guidances. I also liked that in reality it didn’t require a CSV group to create more templates (which I have already seen organizations do!) but instead incorporate these concepts into existing gxp processes (e.g., SOPs, CSV UR templates).”
• “CoC helps a lot about thinking policy in good GMP documentation practices. Thanx for that. This kind of guidance should be mandatory for equipment vendors as well.”

Some respondents expressed concerns about the structure of the document and others noted perceived redundancies. Additionally, there were suggestions to include practical examples within the document. Several respondents mentioned that a code of conduct alone cannot create data integrity; instead, there must be a culture of integrity. PDA is already moving to address many of the suggestions. Another task force is focused on culture within pharmaceutical manufacturing and has previously published the results of a survey (1). Building on these initial results, this Quality Culture Task Force has completed a pilot program to measure quality culture at more than 40 participating companies and expects to publish these results in 2018. The PDA Data Integrity Task Force also expects to publish technical reports on data integrity in 2018, one for laboratory systems and another for manufacturing systems.

Conclusion

Based on the positive results of this survey, the PDA Data Integrity Task Force will continue its work to develop additional tools and resources for the pharmaceutical industry. The Code of Conduct remains available for download.

Reference

1. Patel, P., et al. “Quality Culture Survey Report.” PDA Journal of Pharmaceutical Science and Technology 69 (2015) 631–642.

PDA’s Pharmacopeial Interest Group has been active since 2011. Recently, we took some time to review the Pharmacopeial Interest Group’s five-point mission statement and see how the interest group is meeting these five goals. Below are our findings:

Advocate globally for greater pharmacopoeial cooperation, harmonization (both prospective and retrospective) and working long term toward the ultimate goal of a single international publication

When WHO published a Good Pharmacopoeial Practices draft guidance, the interest group rapidly assembled a task force and sent in general comments in a tight timeframe. Within one day of receiving our general comments, WHO asked for our detailed comments and we sent those in. Clearly, the interest group has a voice and represents the general consensus of PDA’s membership.

Monitor compendial activities and publications and provide periodic reports to RAQAB and PDA members

If you take a look at the group’s PDA Connect^SM site, you will see that our members are kept abreast of updates through this medium. But, there is also a call for members to make posts—so please start doing that. All posts are welcome.

Prepare position papers on compendial initiatives and proposals not being addressed by other PDA Committees

The interest group regularly discusses compendial concerns at face-to-face meetings at PDA’s Annual Meeting and Joint Regulatory Conference with the U.S. FDA. Additionally, PDA is hosting its Pharmacopoeia Conference next May in Vienna, cochaired by Janeen Skutnik-Wilkinson, Staff Associate Compliance & Standards, Biogen, and Susanne Keitel, PhD, Director, EDQM. The theme of the conference is fast-tracking pharmacopeial convergence/harmonization and the future direction of pharmacopeias. We would like to publish more position papers on compendial initiatives, but that needs volunteer input, so reach out to us!

Represent PDA at the USP Stakeholders Forum

We do not always manage to get a PDA-specific person there, although, we try. But any PDA member planning to attend a USP forum is always welcome to contact the interest group and let us know if they are interested in serving as a PDA representative. The interest group’s leaders would work with such a volunteer on where PDA stands with issues under discussion at the meeting and how to obtain formal feedback.

Proactively identify compendial topics and advocate PDA’s position

We don’t always manage to do this, and we need help here, too. If you hear of a compendial issue, let the group know!

Additionally, this interest group recently gave an update to PDA’s Regulatory Affairs and Quality Advisory Board (RAQAB), its Advisory Board umbrella, summarizing the group’s activities. One of the actions identified was to obtain volunteers and “spread the word” among PDA’s membership base, and this update is intended to achieve just that. Anyone wanting to become active in this interest group can contact Denyse Baker at PDA and let us know what you would like to take on.

In summary, the interest group has been and continues to be active. It clearly has a place at PDA and is beneficial to members and to RAQAB and the Board of Directors. There is a need to channel the group’s activities better and grow a set of committed industry volunteers who work with pharmacopeias day in and day out and, therefore, can easily update the group. We hope to hear from those interested in volunteering and we would be delighted to receive feedback from anyone with fresh ideas.

We also want to welcome Anette Yan Marcussen, the new coleader of the interest group. She replaces Karen Ginsbury, who is stepping down. She looks forward to taking the interest group into 2018.

PDA’s New Role-based QRM Certificate Program Offers Courses for all Levels of QRM Involvement

Risk management may not be in your official job description, but do you find yourself assessing risks when making decisions in your day-to-day activities, even if you do not document it formally? Have you participated in a risk assessment and want to improve? Would you like to learn when, where and how to apply quality risk management (QRM)? Are you interested in understanding what good risk-based decision-making means and how it can be achieved?

If you answered “yes” to any of these questions, you will certainly want to take advantage of PDA’s new, first-of-its-kind, role-based “QRM Certificate Program” developed by leaders in QRM. This certificate program is accredited by the Accreditation Council for Pharmacy Education (ACPE) and will be accredited by the Dublin Institute of Technology (DIT).

ICH Q9, Quality Risk Management has been effective since November 2005, yet industry and regulators have still not fully realized its vision and value. While there are various reasons, one foundational explanation is the gap in QRM skills. Since ICH Q9 was published, the primary focus has been on the QRM process and risk assessment tools, while very little attention has been paid to the various roles in the QRM process or developing the skills for each of these roles. Just like different actors have distinct parts in a play, there are different roles in the QRM process, so the program has been designed with this in mind.

This certificate program is a modular training course with tiered tracks (Figure 1). The first series of classes is being offered Dec. 11–14 at PDA TRI.

Figure 1 Foundations for QRM Course

• QRM Foundations Track: This track is designed for all personnel involved in QRM as a participant in risk assessments, QRM facilitator or decision-maker, such as personnel from QA, QC, engineering, validation, production and technical services who are involved in QRM activities. This course is a prerequisite for the tracks listed below.
• QRM Decision Maker Track: This track is applicable to supervisors, managers and directors from disciplines such as QA, QC, engineering, validation, production and technical services, who often make decisions based on the outcomes of risk assessments for their areas of responsibility.
• QRM Application Track: This track is applicable to pharmaceutical professionals engaged in QRM application activities related to CMC for pharmaceutical/biotechnology processes, such as manufacturing supervisors, managers and directors; process development biochemists; microbiologists; cell biologists and molecular biologists; etc.
• QRM Facilitator Track: This track, to be offered in 2018, will be the most comprehensive of the four tracks. It is applicable to individuals expected to be highly skilled and proficient in the entire QRM process and its application, including the use of various QRM tools. QRM facilitators may be involved in various functions across an organization including project management, operational excellence and technical functions.

The benefits that companies can expect to get from this program include:

• Increased alignment in QRM application across the industry
• Reduced internal QRM training efforts
• Improved sharing of QRM application knowledge between companies
• Fully realized QRM application for companies with QRM programs at all maturity levels

For more information, contact Stephanie Ko or David Talmage.

PDA recommended using a risk-based approach to address health-based exposure limits (HBELs) in the presentation, “Key points to recognize quality in Health Based Exposure Limits (HBEL) and associated monograph” at EMA’s June workshop on shared facilities (1). In particular, PDA advocated flexible approaches for products currently manufactured in shared facilities to avoid interrupting the supply of essential medicines.

Hosted by EMA’s Safety Working Party (SWP), this workshop offered industry representatives a chance to discuss the Agency’s Q&A concerning risk-based strategies to prevent cross-contamination in shared facilities (2). The discussions at the workshop were positive and paved the way for continued use of scientifically justified, toxicological, risk-based approaches that rely on documented rationale proportionate to the level of cross-contamination risk.

Background on Shared Facilities

Chapters 3 and 5 of the EU EudraLex Guidelines for Medicinal Products for Human and Veterinary Use require a toxicological evaluation to assess and control cross-contamination risks presented by drug products manufactured in shared production facilities (3, 4). On June 1, 2015, EMA’s regulatory guideline setting Permitted Daily Exposure (PDE) values went into effect for all new human pharmaceutical products. The guideline for existing human pharmaceutical products then went into effect Dec. 1, 2015 (5). Previously, other methods were used to determine an acceptable level of carryover with uncertain levels of patient health protection (6). One of the most frequently used methods was 1/1000 of the minimum daily dose (MinDD). This method has many shortcomings, as has been covered in recent articles (7, 8).

Following implementation of the PDE guideline, EMA issued a Q&A document in response to several open questions (2). While EMA hoped this nonmandatory document would clarify interpretation of the PDE guideline, it reintroduced two criteria that appeared to be a step back. One was the classification of products into two hazard categories; the second related to the continued use of the 1/1000 criteria for nonhazardous drugs. These two points caused significant confusion within industry, and a number of comments have been sent to EMA by industry associations, such as PDA, as well as individual experts.

In its comments, PDA’s Regulatory and Quality Advisory Board (RAQAB) advocated “flexible approaches for products currently manufactured in shared facilities to avoid interruption of supply of essential medicines” (9). PDA recommended use of a scientifically justified, toxicological, riskbased approach relying on a documented rationale. Further, PDA urged EMA to remove references to 1/1000 of the minimum therapeutic dose based on the approach described in the 2015 guideline.

PDA Position Discussed at Workshop

The PDA presentation at the June workshop reiterated the points made in the earlier comments. Following the presentation, attendees raised the following key points in support of PDA’s position:

• Inspectors expect to see the HBEL approach to avoid redundancy of terminology such as “highly hazardous” and the use of 1/1000 MinDD
• Trained and knowledgeable individuals must complete a rigorous methodology to accurately determine a safe/acceptable exposure for a given substance
• Cross-functional users should employ a solid implementation plan to ensure consistent application of practices in complex quality risk management systems (10)
• There are many factors in controlling carryover risks beyond the HBEL, which also need to be done consistently by qualified experts

The discussions at the workshop were positive and paved the way for continued use of a scientifically justified, toxicological, risk-based approach with a documented rationale. While more time is clearly needed for implementation of the PDE/HBEL concepts, future use of toxicological limits is not in dispute. During future inspections, more focus will be given this topic, as well as topics addressed in the Q&A document, such as quality of the PDE documentation, toxicological expertise, responsibilities associated with implementation, and quality of overall GMP risk assessments. A proper and consistent risk assessment of cross-contamination risks has to be available; best practices would include historical process control limits as well as proper training of personnel. The extent of the risk assessment concept must be proportional to the associated risks, which gives some additional opportunities for flexibility to small to medium-sized enterprises with lower cross-contamination risks.

References

1. Barle, E.L. “Key points to recognize quality in HBEL and associated monograph.” Presented at EMA Stakeholder guidance workshop on shared facilities, London, June 20–21, 2017.
2. Questions and answers on implementation of risk based prevention of cross contamination in production and ‘Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities,’ European Medicines Agency, December 2016.
3. European Commission, EudraLex: “The Rules Governing Medicinal Products in the European Union, Part I-Basic Requirements for Medicinal Products. Volume 4. EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. Chapter 3: Premises and Equipment,” August 2014.
4. European Commission, EudraLex: “The Rules Governing Medicinal Products in the European Union, Part I–Basic Requirements for Medicinal Products. Volume 4. EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. Chapter 5: Production,” August 2014.
5. Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities, European Medicines Agency, November 2014.
6. Fourman, G.L. and Mullen, M.V., “Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations.” Pharmaceutical Technology 17 (1993): 54-60.
7. Lovsin Barle E., et al. “Comparison of Permitted Daily Exposure with 0.001 Minimal Daily Dose for Cleaning Validation.” Pharmaceutical Technology 41 (2017): 42-53.
8. Walsh, A., et al. “Cleaning Limits—Why the 10-ppm and 0.001-Dose Criteria Should be Abandoned, Part II.” Pharmaceutical Technology 40 (2016): 45-55.
9. PDA to EMA, May 25, 2017
10. Olson, M. et al., “Issues and approaches for ensuring effective communication on acceptable daily exposure (ADE) values applied to pharmaceutical cleaning,” Supplement. Regulatory Toxicology and Pharmacology 79 (2016):S19- S27.

As always, relevant interest groups will meet for the first two days of the 2017 PDA/FDA Joint Regulatory Conference. Below is a schedule of interest group meetings falling under the Regulatory Affairs and Quality Advisory Board (RAQAB).

Monday, Sept. 11

5:30 p.m. – 6:45 p.m.

• Quality Systems Interest Group
• Supply Chain Management Interest Group
• Quality Risk Management Interest Group
• Pharmacopeial Interest Group

Tuesday, Sept. 12

5:30 p.m. – 6:30 p.m.

• Regulatory Affairs Interest Group
• Inspection Trends Interest Group
• GMP Links to Pharmacovigilance Interest Group
• Technology Transfer Interest Group

Barriers to innovation during lifecycle management of a product are multiple. They notably include the complexity of the current post-approval change (PAC) regulatory environment. Recognizing the need for action, several international organizations are currently working toward the global convergence of regulatory requirements for PACs.

In 2014, ICH began its work on ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management. The main objective of ICH Q12 is to facilitate predictable and efficient PAC management in order to support innovation and ensure reliable product supply. PDA launched its Manufacturing Science and Operations Program (MSOP) in 2014 and offered a Manufacturing Science workshop addressing the barriers for implementation of PACs the following year.

Shortly before the workshop, a team of highly motivated PDA volunteers gathered to form a task force and set out to develop a new PDA technical report that would supplement ICH Q12 by offering specific solutions to facilitate innovation and industry collaboration. The task force later expanded its portfolio of planned activities to include other documents covering related topics and tools. New team members joined. And after a face-to-face meeting in January 2016, the task force decided to continue the journey under a new name and program: “Post-Approval Changes: Innovation for Access to Medicines^SM,” or PAC iAM.

The PAC iAM program has the following objectives:

• Bring awareness to current challenges and enable stronger collaboration among opinion leaders and key stakeholders
• Foster a science- and risk-based approach to PAC management and regulatory decision-making for global product quality, safety, and efficacy assessments
• Encourage international convergence/standardization in PAC management in a manner that can foster and enable mutual reliance between regulatory authorities
• Manage PACs through the use of an effective Pharmaceutical Quality System (PQS)

Last year turned out to be a very busy year for the PAC iAM team. First, the team raised awareness of the issue in a call to action, inviting the broader pharmaceutical industry and regulatory community to join efforts in tackling the “wicked problem” of drug shortages (see “Drug Shortage is a “Wicked Problem’” by Anders Vinther).

Members of the task force also authored a series of Points to Consider (PtC) papers on technical product lifecycle management for publication in the PDA Journal of Pharmaceutical Science and Technology. The first PtC paper, entitled “Communication and Knowledge Exchange between Marketing Authorization Holders and Health Authorities,” was published in January. The second PtC paper, entitled “Pharmaceutical Quality System Effectiveness For Managing Post-Approval Changes,” published in February, elaborates on the role of the pharmaceutical quality system (PQS) in supporting effective change management. The paper describes how opportunities outlined in ICH Q10: Pharmaceutical Quality System can be used to manage product and process changes within the PQS to reduce regulatory reporting requirements. A third PtC paper covering Quality Risk Management and knowledge management for PACs is currently in development.

In the fall of 2016, members of the task force formed a team to work on a PAC technical report that focuses on the practical aspects of PAC management using science- and risk-based approaches and illustrates how an effective PQS can support change management. It will be based on best practices across the industry. The technical report team intends to publish examples of Post-Approval Change Management Protocols (PACMPs) that can be used for various manufacturing changes involving a range of product types.

Finally, in December 2016, PDA launched a survey on PACs to collect data on what resources companies expend handling PACs in the current regulatory environment.

In light of all these activities that began in 2016, what is planned for 2017? Apart from the wealth of ongoing activities outlined above, PDA intends to offer a PAC workshop immediately following the 2017 PDA/FDA Joint Regulatory Conference in September.

PAC iAM has taken us on an exciting journey so far that will surely continue. To learn more about the PDA PAC iAM program, please visit our website.

As always, interest groups falling under the Regulatory Affairs and Quality Advisory Board (RAQAB) will convene at the 2017 PDA Annual Meeting. Below is the schedule for the RAQAB interest group meetings, which are open to all conference registrants.

Monday, April 3

4:15 p.m.–5:30 p.m.

• Management of Outsourced Operations Interest Group

Tuesday, April 4

4 p.m.–5:15 p.m.

• Quality Risk Management Interest Group
• Technology Transfer Interest Group

Last June, EMA published the draft document, Questions and answers on production of water for injections by non-distillation methods – reverse osmosis and biofilms and control strategies. EMA often uses such Q&A documents to clarify the Agency’s position, including possible regulatory requirements, in response to changes in directives, guidances, or in this case, a pharmacopeial monograph, specifically the European Pharmacopoeia’s (EP) Water for Injections (WFI) monograph (0169).

This revision has been long-awaited. The USP has allowed purification, along with distillation methods, to be used to produce WFI for many years, while the EP only allowed the use of distillation to produce WFI. Those in the pharmaceutical water community welcomed this revision with great excitement and optimism. In response to the EMA document, PDA assembled a team of PDA water experts to review and comment on it.

In its response, PDA fully supported the implementation of non-distillation methods for WFI production into the European regulatory framework, and endorsed the premise that non-distillation technology for producing WFI should produce water equivalent in quality to that produced by distillation.

The team had concerns with many of the approaches specified in the Q&A document, however, deeming them not science- nor risk-based. In fact, the team considered some of the requirements to be above and beyond what is in the EP monograph.

PDA recommended referencing existing technical documents, such as PDA’s technical reports for best practices, and allowing manufacturing firms to make risk-based decisions based on science instead of limiting firms through overly prescriptive regulations or monographs. The cited examples were rapid microbial methods and online vs. offline total organic carbon methods. The commenting team further stated that “this document should clarify monitoring methods which are reactive vs. control methods which are proactive.” Additionally, the team recommended including requirements for distribution and storage systems that permit manufacturers (as long as they include appropriate documentation) a choice of routine sanitization approaches, such as steam, hot water, ozone, or other chemicals, and avoid requiring complete redundant approaches or steam in all cases.

Read the commenting team's letter to EMA here.

Temperature excursions and delays at airports are major concerns for companies shipping temperature-sensitive pharmaceutical products by air. In light of this, last fall, the International Air Transport Association (IATA) presented their Center of Excellence for Independent Validators (CEIV) certification program to the European steering committee of PDA’s Pharmaceutical Cold Chain Interest Group. IATA represents 265 airlines that account for approximately 83% of total air traffic. The CEIV certification program was developed in 2014 as part of an effort to harmonize the air transport industry’s practices for shipment of pharmaceutical product and accommodate the pharmaceutical industry’s GDP expectations. This program emphasizes the importance of having defined quality and risk management systems in place to address requirements coming from global regulators. IATA intends to provide the pharmaceutical manufacturing industry a harmonized standard for handling and transporting healthcare products worldwide through a network of CEIV-certified airlines, airports, ground handling agents, trucking companies, and forwarders.

The interest group’s European steering committee welcomes this initiative as a valuable effort in the joint quest of the airline and pharmaceutical industries to deliver safe healthcare products to patients. This program intends to deliver quality and risk management systems in the logistics industry designed according to mainstream GDP regulatory documents (MHRA, USP, EMA). Considering the increase in the complexity of the pharmaceutical supply chain, a network of CEIV-certified suppliers would undoubtedly enhance controls and visibility throughout the air freight industry.

More information about the program can be found here.

More than 100 PDA volunteers spent nearly 675 hours developing responses summarizing PDA’s positions on a variety of draft regulations in 2016. In some cases, small teams of three to five experts came together to respond quickly to a pertinent guidance document with only a 30- or 45-day comment window. In other cases, a task force of 16 or 17 members worked for several months to reach consensus on the finer points of a regulation that warranted a thorough response from PDA. In every response, the comments focused on the important scientific/technical concerns posed by the proposed regulation, notably impact on patient protection and product quality.

As shown in Figure 1, PDA responded to comments from multiple regulatory agencies around the world, primarily to documents published by the U.S. FDA, EMA, the UK MHRA, and WHO. PDA is open to responding to documents from other regulatory agencies provided they fall under the Association’s specialized areas of aseptic processing, validation, manufacturing, biotechnology, GMP/compliance, supply chain, and quality systems, among others.

Figure 1 PDA Regulatory Commenting Activity

Each regulatory agency has a different process and timeline for collecting comments. Sufficient lead time for comments is one of PDA’s criteria for determining whether or not to comment as the Association relies on volunteers with appropriate expertise. These volunteers must then be available during the commenting period. PDA’s internal balloting procedures for regulatory comments make it difficult to respond to regulatory proposals with commenting windows less than 60 days.

One of the important principles of PDA comments is to facilitate a common understanding and approach. Commenting task forces usually cite existing standards and technical guidance, encouraging the regulatory body in question to use these within the document. When applicable, the comments reference scientific principles right out of PDA’s technical reports. At a recent PDA workshop in Dublin, both FDA and EMA investigators stated their support for referencing PDA technical reports in responses to regulatory documents. PDA comments are also valued by regulators. At times, PDA has been invited directly by authors from individual regulatory agencies to comment on draft guidelines. One agency even asked PDA to submit additional detailed responses on specific issues following the submission period.

The Regulatory and Quality Advisory Board (RAQAB) also tries to determine the impact PDA’s official comments have on the final regulatory guidance documents. Although it could be several months, or even years, between the open comment period and publication of a final guideline, PDA retains a record of the Association’s comments on each specific document. Task force members then compare the draft and final versions of the regulatory document to evaluate how many of PDA’s comments were incorporated into the final version. From these observations, RAQAB has ascertained that about 50% of PDA’s comments are accepted on average. Still, results for individual regulatory agency documents vary.

Once a task force has completed its draft, the responses are balloted by one of the three PDA Advisory Boards—Regulatory and Quality Advisory Board (RAQAB), Science Advisory Board (SAB) Biotechnology Advisory Board (BioAB)—with RAQAB balloting the majority. In 2016, RAQAB balloted 13 of the 16 commenting ballots. Following resolution of any Advisory Board questions, the responses proceed to the Board of Directors for ballot. Only after this final step can the document be considered the official position of the Association. Through this process, PDA ensures the highest level of technical content in each response and also consistency with PDA’s values and mission.

PDA commenting task forces are open to any member with an interest and expertise in the topic of the draft publication. Requests for volunteers are sent out to the Advisory Boards and frequently posted to PDA Connect^SM in the most relevant interest group forum.

Overall, the commenting process is one way for all members to participate in the PDA mission of advancing manufacturing and regulatory science and support the PDA values of science, integrity and inclusion.

The PDA Letter reached out to the new Regulatory Affairs and Quality Advisory Board (RAQAB) Chair Jeff Broadfoot, Director, Corporate Quality Compliance, Emergent BioSystems, and Vice-Chair Jackie Veivia-Panter, Consultant, and asked them a few questions about their plans for the RAQAB.

PDA Letter: What are some of your overarching goals as the new co-chairs of the RAQAB?

Jeff and Jackie: First, we want to be proactive in identifying significant emerging regulatory and compliance issues, and then provide advice to the Board of Directors so that PDA can mobilize resources to support PDA’s membership.

We also plan to develop a robust succession plan for RAQAB in order to ensure we have the global and diverse knowledge available to meet the needs of ever-expanding and changing regulations.

And we will engage with PDA members about RAQAB’s role by communicating the benefits of RAQAB and understanding the needs of PDA members. This includes collaborating with PDA chapters, providing articles for the PDA Letter and PDA Journal, and reaching out to interest group members.

PDA Letter: What experience do you bring to RAQAB? Both from industry as well as from being members of RAQAB?

Jeff: I’ve been in QA/QC in the pharma industry for almost 25 years in facilities manufacturing everything from medicated ointments and creams to tablets and capsules to biologics and parenterals. I’ve been in management for about 15 years. I’ve covered a lot of ground in that time and understand the complexity of making pharmaceuticals, as well as the day-to-day challenges of running a manufacturing site. I’ve been a member of RAQAB since 2009 as the Canada Regional Rep. I spent the last three years as Vice-Chair before becoming Chair in July of this year. That experience has given me a great appreciation for the role that industry can and does play in shaping both the regulatory environment and the concept of quality.

Jackie: I have over 25 years of experience in pharmaceutical quality. My experience is in R&D and Operations in many aspects of the pharmaceutical quality system. Much of my time has been spent improving quality systems and ensuring regulatory requirements are met. This will be the first year as a co-chair on the RAQAB and I am really looking forward to it! I have learned so much from all the members and past chairs. It will be a great opportunity to continue the great work established and ensure improvement to meet the needs of the industry.

PDA Letter: What topics will RAQAB address in 2017?

Jeff and Jackie: RAQAB will continue to work on hot topics such as data integrity, post-approval changes, and quality culture metrics.

PDA Letter: What are you most looking forward to as co-chair?

Jackie: I have enjoyed being a member of the RAQAB. The breadth of knowledge within the RAQAB is incredible and has really challenged me to grow and learn. I am looking forward to continuing this and helping the RAQAB and its members succeed in their mission.

Jeff: One of my favorite quotes says, “If I have seen further it is by standing on the shoulders of giants.” There really have been some giants that have led RAQAB. I’m looking forward to building on their successes.

The state of regulatory postapproval change (PAC) processes worldwide can be characterized as complex and inconsistent for many reasons, such as varying classifications, different submission requirements, and implementation timelines, all of which creates unintended disincentives for manufacturers to continually improve and technically innovate or forces companies to maintain parallel inventories.

Many companies find it easier to postpone improvements to facilities, processes, and analytics or simply refrain from planning for advancements at all in order to avoid the intricate nature of implementing such changes, especially for product registered in multiple countries.

Other companies that do implement even simple changes might choose to segment their inventories over many months in order to meet regional requirements and avoid filing changes in all regions served. Attendees at the recent 2015 PDA/FDA Manufacturing Science Workshop shared several examples of this problem. In the most extreme case, a company maintained more than 30 versions of the same product in parallel due to differences in timing of country-specific regulatory approval processes.

Both strategies—upgrade/improvement avoidance or parallel inventories—are fraught with serious consequences that can contribute to the problem of drug shortages. Technology avoidance can lead to drug shortages that could have been mitigated effectively through process or technology improvements. Segmentation of inventories, on the other hand, makes it more difficult for a manufacturer to accommodate sudden increases in product demand in one of these segments. Both strategies can result in an increasing risk of errors in releasing nonconforming product to a country, and possibly even resulting in cGMP noncompliance.

Industry and Regulators Responsibilities

At the workshop there was a general agreement by regulators and industry alike to see the fulfilment of the three objectives found in International Conference on Harmonisation (ICH) quality guideline Q10: Pharmaceutical Quality System:

• Achieve product realization
• Establish and maintain a state of control
• Facilitate continual improvement.

So how can the industry move in this direction and not let the complexity of PAC regulatory processes serve as a roadblock?

First, workshop attendees agreed that the burden of ensuring safe and compliant PACs falls on the companies themselves. As such, manufacturers must ensure that effective change management processes are in place as part of the pharmaceutical quality system (PQS) within their companies. The process of evaluating PACs must include all relevant functions/organizations in the company, leverage country-specific competences in affiliates, and bundle relevant changes as much as possible. Workshop attendees also agreed that all companies must develop lifecycle management plans and global change protocols as elements of an effective PQS.

Nevertheless, attendees believed that regulatory authorities around the world are responsible for creating a less complicated global system that allows companies to make necessary process improvements. The World Health Organization (WHO) resolution 67.20, which describes the balance between regulatory oversight and availability/access to drug products, was cited as an important guiding principal.

Attendees discussed how the regulatory burden can be reduced for both regulators and industry while encouraging PACs that aim to achieve ICH Q10 objectives. In addition, attendees cited the importance of regulatory authorities relying more on each other for science- and risk-based quality, safety and efficacy assessments of PACs rather than demanding redundant local assessments.

Workshop attendees also mentioned certain worthwhile regulatory tools, such as “expanded comparability protocols” (eCPs), as ways to facilitate postapproval changes.

Attendees pointed out that solving the quagmire of global PAC regulations is difficult at a time of a rapidly growing globalization within the industry, but increasing parochial demands of health authorities.

ICH Q12 a PAC Solution?

A unified platform for addressing the challenges and complexity of managing PACs is forthcoming from the working group for quality guideline Q12: Technical and Regulatory Considerations for Pharmaceutical Lifecycle Management.

ICH Q12 will facilitate alignment of different regions and countries on a common definition and set of established conditions. The document should define a lifecycle management strategy and harmonizing on a foundational framework for postapproval change management, including how an effective PQS can be leveraged to reduce the regulatory burden of implementing changes globally.

Moheb Nasr, Vice President, CMC Strategy, GlaxoSmithKline, who is rapporteur for the document, delivered a presentation covering ICH Q12 at the workshop. One desired objective for ICH Q12 is for it to also be adopted and used in non-ICH regions. This is important as many companies market their products globally, thus solutions to PAC complexity must take a global approach to be efficient.

PDA’s PAC Solutions

PDA is taking an active role in providing input to the ICH Q12 working group to facilitate global harmonization through a science and risk-based approach, building on our 10,000+ strong membership.

In addition to discussions through workshops, surveys and discussion forums, PDA’s activities are currently focused on the following key topics:

• PAC challenges awareness through promulgation of practical examples
• Lifecycle management (LCM) plans to enable effective PAC planning and implementation
• Common technical improvements and innovation facilitated by “global change protocols” (gCPs)
• Leveraging a robust PQS to effectively manage PACs

PDA will develop reports and working papers on each of these topics and tools.

The LCM Plan will provide an opportunity for the marketing authorization holder (MAH) to prospectively provide information to the regulator regarding their plans for managing the product during its commercial life. It can serve either as a regulatory agreement between the MAH and the regulatory body, or as a mechanism for early communication and prospective planning of post approval changes.

The gCP is a detailed protocol that describes one or multiple PAC(s), including rationale for the change, risk assessment, proposed studies needed for validation and comparability, as well as acceptance criteria. The gCP will provide the possibility to standardize certain types of PACs globally based on solid scientific data and agreed upon requirements. The goal is to expedite the change through the regulatory systems of different countries.

In order for LCM Plans, gCPs and leveraged PQS to be successful, it will be important to achieve proactive planning and transparency with health authorities as early as possible. It will also be important for health authorities to further drive reliance on each other’s approval processes.

A successful outcome will result in more postapproval changes implemented via a standard gCP without prior approval reporting and increased reliance on companies’ robust PQS. This ability will result in faster approval or downgrading of reporting for changes that will enable or incentivize companies to incorporate new technologies, improve capability, process control, and enhance product availability.

Additionally, standard implementation and similar reporting requirements and timelines to approval globally will decrease the current complexity of varying PAC processes, ultimately reducing drug shortages and promoting ICH Q10 objectives.

The authors invite those interested in helping PDA’s PAC activities to contact PDA if interested in volunteering in this space.

[Editor's Note: On Oct. 9, EMA held a drug shortage workshop with attendance by National Competent Authorities, U.S. FDA and JPMA observers, industry associations and patient and healthcare organizations. At this workshop, PDA presented its plans and highlighted the importance of addressing lifecycle management as being key to ensure supply continuity. Additionally, PDA is in the process of developing a survey to solicit input on best practices and how companies achieved successes with PACs.]

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