ipq international pharmaceutical quality€¦ · · 2015-11-04united states updates in brief - p...

MONTHLY UPDATE - SEPTEMBER 2015

GMP/INSPECTION

• FDA’s “New Inspection Protocol Project” Will Impact How Inspections Are Planned, Conducted, Reported On, andAssessed and Offers a Potential Global Model................................................................................................................................3

• Phased Implementation, Reporting Burden Among Industry Focal Points in Initial Feedback on FDA’s QualityMetrics Draft Guidance........................................................................................................................................................................13

UNITED STATES

UPDATES IN BRIEF - p. 55

U.S CMC: • Woodcock at Congress on Biosimilars • New OPQ Director • Addendum to ICH M7 •Controlled Correspondence for Generics • Generic Drug Physical AttributesU.S GMP: • Drug Destruction Final Rule • FDA Overseas Offices • Sun Drug Approval Rescinded •India’s Polydrug API Ban • Canada’s CMI Import Ban • Impax Warning Letter Resolution

EUROPE CMC: • Pre-Authorization Procedural Advice • CEP Requirement Revision • EDQM Technical Guide EUROPE GMP: • EU GMP Implementing Act • EU RTR Guideline • EMA-WHO Information Sharing •APIC ICH Q7 Guide Revision

INTERNATIONAL GMP: • WHO Notice to India’s Svizera Labs • Health Canada Lifts Apotex Ban • India Strengthens Drug Regulation

IPQwww.ipqpubs.com

INTERNATIONAL PHARMACEUTICAL QUALITYInside the Global Regulatory Dialogue

VOL. 7, NO. 5

FDA WARNING LETTERS AND RECALLS POSTED IN SEPTEMBER - p. 61

INTERNATIONAL

CMC/REVIEW

• Stress Studies Are Playing Key Role for Roche/Genentech in Assessing Biomanufacturing Process Site Transfers..36

• Analytical Methods Handoff Pivotal to Successful Manufacturing Site Transfer, and Multiple Pitfalls Lurk, BCSConsultant Stresses at Latin America CMC Strategy Forum........................................................................................................47

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EDITOR’s NOTE: Welcome to IPQ’s “Monthly Update” on key CMC/GMP developments in the US, Europe, and internationally. The IPQ family of publications includes “The News in Depth” and”Updates in Brief” on our website as they occur, “Weekly News Alerts” sent via e-mail, and the “Monthly Update.” IPQ’s suite of offerings support our mission of helping readers under-stand, engage in and respond to the dialogue and developments around evolving and harmo-nizing the regulation of drug and biologic quality and manufacturing. Subscribers and license holders to IPQ have access to all of these sources of cutting-edge news and in-depth analysis as well as to the full IPQ archives. Visit IPQpubs.com for further information.

INTERNATIONAL PHARMACEUTICAL

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MONTHLY UPDATE - SEPTEMBER 2015MONTHLY UPDATE - SEPTEMBER 2015 MONTHLY UPDATE - SEPTEMBER 2015

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INSIDE THE GLOBAL REGULATORY DIALOGUE™

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UNITED STATESFDA’s “New Inspection Protocol Project” will Impact How Inspections Are Planned, Conducted, Reported On, and Assessed and Offers a Potential Global ModelFDA’s Center for Drug Evaluation and Research (CDER), in conjunction with the agency’s field organization, has developed and is piloting a new inspection protocol that will impact the scope of what investigators are looking for and how they are assessing and reporting what they find.

The “New Inspection Protocol Project” (NIPP) expands the investigator’s focus beyond uncovering specific cGMP violations to assessing the overall state of a manufacturer’s quality systems and operations – the strengths as well as the weaknesses.

The goal is an inspection report that: ● is better organized, more transparent and searchable, and less subjective ● allows for easier evaluation, measuring, tracking, and comparisons ● can be produced in a semi-automated fashion ● focuses on more than violations, and ● is more useful in driving manufacturing improvements.

FDA views its protocol effort as a potential foundation for a more internationally harmonized inspection approach and improved inter-agency communication in line with the ICH Q8-12 guideline series.

At a breakfast session at the PDA/FDA joint regulatory conference in September in Washington, DC, CDER Office of Pharmaceutical Quality (OPQ) Office of Process and Facilities (OPF) Acting Deputy Director David Doleski provided the background, current status and future plans for NIPP and how the project fits into the larger quality regulatory paradigm shift the agency and OPQ is working to accomplish.

Three Protocols Being Piloted

The NIPP project began in mid-2014 as part of CDER’s effort under Janet Woodcock’s direction to create more effective and improvement-friendly quality regulatory structures and processes.

In accord with the center/field program alignment initiative (see IPQ “Monthly Update” December 2014, pp. 10-16), NIPP is seen as an opportunity for closer collaboration between inspectors and the CDER staff doing the evaluations – providing a common language and measurement tools.

As such, the NIPP steering committee includes high level management from both CDER and the Office of Regulatory Affairs (ORA).

Three subgroups were formed to develop the protocols, corresponding to the three major types of drug inspections: ● pre-approval ● surveillance (GMP), and ● for-cause.

Doleski along with his OPF colleague, Acting Director Christine Moore, are leading the pre-approval subteam.

The three inspection protocols are similar, Doleski explained, and include the assessment of GMP compliance and documenting the state of quality in a manufacturing facility. The preapproval protocol also covers evaluating conformance to the submitted drug application, and the for-cause protocol includes gathering evidence related to enforcement actions.

A common goal for each of the inspection types is to develop common language and produce an organized inspection report that includes numerical scores for each of the elements being assessed.

In his presentation at the PDA/FDA conference, Doleski discussed: ● the remit provided to the teams by the steering committee ● the NIPP goals and approach ● the components of the program ● the status of the pilot ● next steps, and ● the implications for both the agency and industry (Doleski’s complete remarks on NIPP at the conference are provided below).

The steering committee charged the subgroups with developing an approach that would increase the effectiveness and efficiency of the inspections while maximizing the return on investment of the human and financial resources involved.

In pursuit of this goal, the teams were asked to develop standardized inspection reports that would provide analyzable data to inform ongoing assessments of the state of manufacturing quality using a methodology that produces consistent grading within and between sites – essentially shifting from a subjective to a semi-quantitative reporting process.

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The new assessment process is being designed to track and improve performance as well as recognizing and rewarding firms that have more advanced quality operations.

Protocols Include Defining Performance Levels, Questionnaire

The new protocol, Doleski explained, allows for different performance levels to be described. Investigators will assign numeric scores to each inspected element and later aggregate the scores for particular systems.

Also part of the protocols are example ratings developed through real-life situations that investigators are being trained on for calibration purposes. The performance levels are harmonized between the preapproval and surveillance programs.

Doleski pointed out that these assessments are being performed in addition to what is “normally” done during an inspection, and that while the 483 observations can be related to the scores for the particular systems, that “they are not necessarily cause-and-effect…not necessarily linked.”

An important aspect of the new inspection protocol is the inspection questionnaire, consisting of a number of questions that are associated with each of the inspection elements.

The questions are intended to guide investigators on what areas to cover and the information that needs to be captured and to facilitate the inspection and subsequent report generation.

Discussing the development of these questionaires and how they fit into the program alignment effort at a conference in the fall of 2014 (ibid.), ORA Assistant Commissioner for Operations Ellen Morrison explained that they will allow investigators “to capture consistent metrics” so that those reviewing the inspections “don’t have to read a 150-page report at the end of the day that is virtually unstructured data.”

She added that there will also be joint field/center training efforts aimed at ensuring that investigators are better prepared to conduct inspections by having a better understanding of the manufacturing process prior to going on-site.

Phase I of the Pilot Nearing Completion

As of the 2015 PDA/FDA meeting in late September, ten inspections had been completed under each of the three protocols. All Phase I inspections are expected to be completed during October. The inspections have focused

on sterile products produced by aseptic manufacturing, representing the highest risk category.

Phase I was designed to gauge the feasibility of the protocol approach and to assess and refine it, while keeping the standard inspection process and assessment separate.

The initial feedback on Phase I from investigators who participated has been “very positive,” Doleski commented. Investigators found the protocols “very helpful” in guiding the course of the inspections, and some expressed a desire to use the protocols for inspections outside the pilot.

Once the data is evaluated, the intent is to start Phase II at the beginning of 2016. Phase II will expand the approach to other product types, greatly increase the number of inspections, and use accumulated data to create a library of practices and associated ratings.

Desired outcomes from the new approach include more consistent inspections, rationalized inspection frequency, and sharing rankings with firms being inspected.

The protocols will facilitate the same depth and breadth of coverage across inspections, Doleski explained. As the data is accumulated, sites that demonstrate GMP compliance “above and beyond” basic expectations “will benefit from fewer inspections.” In the long term, he noted, the agency’s goal is to share the inspection scores with the inspected companies to help drive improvement.

Q&A Explores Protocol Structure and Function

In the Q&A following Doleski’s talk, clarification was sought on the inspection protocol document and the associated questionnaire – their structure and function and how they are being used.

Parexel Consulting’s Peter Smith, a former FDA investigator and compliance official, began the discussion by commenting that “this sounds like a combination of Turbo-EIR and checklists.” He queried if “that is what we are going to see as an outcome?”

“I would definitely say that it is not a checklist,” Doleski responded. “The questions that go into these inspection protocols are meant as questions to the investigator to drive their assessment [and] to ensure consistency amongst different areas of coverage.”

Doleski commented that some areas – for example, the ICH Q10 concepts of management review and continuous


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improvement – are areas “that perhaps may not have been covered specifically in the past by the investigators. So we are going to drive consistency in coverage in those areas.”

The OPQ official acknowledged that during the development of the protocol, the “natural concern” of investigators was that the team was going to develop a checklist.

“That was one of the greatest concerns on the part of ORA,” he commented. However, “now that we have the inspection protocol out there, people are comfortable with it. They are using it. This is not a checklist. It is a manner of arriving at consistent coverage of particular areas.”

Regarding the Turbo-EIR comparison, Doleski said, “I am not sure that is a favorable comparison. What we are hoping to do is to structure the EIR in a more consistent manner so that you can more easily find the particular areas of coverage that you are looking for…. I think you are going to find that it is going to be a much more favorable format than Turbo-EIR ever was.”

In response to another question from the audience requesting clarification regarding the questionnaire Doleski had mentioned during his talk, the CDER official explained that it would be used for inspection planning and not as a list of questions to be asked during the inspection.

“The basic idea is that it is supposed to drive the final execution of the inspection, but also facilitate the capture of the information generally from the inspection,” he pointed out. “It is something that is generally going to affect their inspection plan for the day. We have tablets that are being used to capture the information [electronically]. They are probably going to be capturing this information after the day is done.”

Protocol Finalization and Sharing Addressed

Doleski was also asked if the inspection protocol would be shared with industry.

“We are not sharing the protocol with industry at this time,” Doleski said, “because we are still developing it.” The NIPP teams “have a good sense of what this protocol should be. We have developed the protocol. But we realize that we are going to have to refine it.”

Once the protocol is finalized, CDER will revisit the issue of making it available to industry.

“Certainly that is something that we have in mind down the road,” Doleski commented. “Right now we are just

experimenting with it and seeing if the concept is feasible.”

Regarding sharing the information in the library of practices that represent different performance levels, Doleski foresees “that ultimately we will share examples of performance at the different levels. We may not share the library itself, but typical examples of what would drive a particular rating at a performance level.”

A participant asked when the agency anticipates finalizing the protocol.

Doleski answered that Phase I of the pilot and its assessment was scheduled to be completed by the end of this year. The teams will examine all of the data that has been captured, and then go on to Phase II, probably beginning in January.

Phase II will involve “a much larger number of inspections,” he explained. Once those are performed and the results analyzed, “at that point we can come up with a final version that will be used across the board for preapproval and surveillance inspections. I would say that it is possible that we will be done sometime next year. But that is to be determined.”

A Global Model?

Industry consultant Frank Hallinan, a former Irish Medicines Board (IMB) inspection topsider, asked if there was any input from other regulators on the protocol and how it may impact, for example, the joint inspection process with Europe.

Hallinan noted that “we hear these days about interactions between different regulatory groups in the US and Europe and other places. And the US is now part of PIC/S. Have you discussed this program and this change to how you do inspections with any of your global partners? If so, what is their feedback?”

Doleski commented that “after we develop this inspection protocol and it becomes common, we think that this will facilitate sharing of information among different regulatory regions.”

FDA, he said, is “hoping that having this more standardized format and having more objective assessments of particular elements that are covered during the course of the inspection will be a basis of sharing our inspection reports and perhaps ultimately relying on inspections of other regulatory authorities by the use of this instrument.”ultimately relying on inspections of other regulatory authorities by the use of this instrument.”

However, the FDA team has not yet engaged with other




regulatory authorities on the effort “because we feel that the inspection protocol is still under development,” In turn, “as we progress throughout this pilot, we may engage with other regulatory authorities at such time.”

Hallinan responded that “as an ex-regulator with a European agency, I think that is a pity, because I think that if I was still at the agency I would much rather hear about this in the development phase rather than hear about it as a fait accompli afterword.”

Relationship to Metrics Initiative and Q10 Querried

A participant asked about how the new inspection protocol project relates to the agency’s quality metrics initiative (pp. 13-35 and IPQ “Monthly Update” July-August 2015, pp. 11-27).

Doleski commented that the quality metrics and inspection protocol initiatives have not been directly connected to date. However, he said, “as the quality metrics initiative develops, I think at a future point we may be able to incorporate quality metrics information into the inspection protocol.”

Another questioner probed into the relationship between ICH Q10 and NIPP.

The OPQ official responded that assessment of the ICH Q10 elements regarding management commitment, allocation of resources, continual improvement, and management review are “very important” components of the inspection protocol.

Doleski also noted that, while the inspection protocol has been shared with the Center for Biologics Evaluation and Research (CBER), at this time CBER is not part of the project. “Down the road we hope to involve them to a much greater extent in this project," he said.

OPQ’S DAVID DOLESKI ON THE NEW INSPECTION PROTOCOL PROJECT

At the PDA/FDA Joint Regulatory Conference, CDER OPQ Office of Process and Facilities (OPF) Deputy Director David Doleski provided insights into CDER’S New Inspection Protocol Project (NIPPP). In his pre-sentation, Doleski discussed: ● the background ● the remit provided to the teams by the steering committee ● the goals and approach ● the components of the program ● the status of the pilot ● the next steps, and ●the implications for both the agency and industry.

I would like to talk about the New Inspection Protocol Project. I will give you the background of the project. We have been working on this for the last year-and-a-half. We have not shared a lot about this publicly. But I am going to give you some of the basic elements of the protocol. And I am going to tell you about some of the pilot programs that we have underway and what we are expecting to see as a result of the project. I will compare what we are currently doing with inspections to the future state of inspections under the NIPP.

Background

For the last many years, FDA has done inspections that are very focused on violations. We are focused on employee practices, equipment and facility problems, lack of process control, and other inefficiencies. After the inspection, what we do is write up an inspection report that is a narrative. It has a basic organization, but it is something that is not easily analyzable. For someone who is not familiar with the inspection, it is somewhat difficult to gather quick information about the nature of the violations.

So what we are hoping to do in the future under the new inspection protocol is to have an inspection product that focuses on measuring and describing the state of manufacturing quality in the inspected facility. So the inspection is going to include analyzable assessments to track and improve performance of the manufacturing facility. We are hoping to have a clear set of requirements that may lead to a better utilization of information by the inspection authorities.

What is idea behind the inspection protocol? Basically a successful inspection will be one that adds value and encourages manufacturing and quality. It is not just about detecting the problems. It is also about finding what is going well within the facility that is being inspected.

Inspections should yield semi-quantitative assessments of the state of manufacturing quality at the inspected

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facilities. It should not just be subjective information. It should be something that is measurable over the course of the inspection. While continuing to document the observed deficiencies, inspections should also focus on what is going well with that company.

What we are doing is we are changing our focus to not only find problems uncovered during the course of the inspection, but also to find things that are going well within the company being inspected. It is an opportunity to document observed deficiencies and also identify practices that exceed basic compliance.

Lastly, the inspection should be an opportunity to collaborate with ORA, the folks who are performing the inspection, and CDER, which evaluates inspection results. It should be an opportunity to talk about a common language for describing inspection reports – something that is easily measurable between the two sides.

The New Inspection Protocol Project started about a year-and-a-half ago. It was initiated by Dr. Woodcock in CDER, and involves high level leadership from both CDER and ORA. There is an overall steering committee that involves the top management from CDER and ORA, which has provided the overall direction behind this project.

We have three different subgroups that are working on the new inspection protocol. The first subgroup is working on the preapproval inspection protocol. Christine Moore and I are the project leads for this initiative. We are working on protocols that pertain to drugs that are under review and will undergo preapproval inspections.

The second group is involved in developing inspection protocols for surveillance inspections. These are for products that are currently on the market to assess the quality of the product.

The last inspection protocol is the for-cause inspection subgroup. Tom Cosgrove, Rick Friedman and Tim Pohlhaus are involved in this project. This is basically to develop standards for evidence related to enforcement actions.

These are the three inspection protocols that are under development.

Steering Committee Remit

When we first launched this initiative, the steering committee gave us a number of goals to accomplish over the course of the project. The goals were:

● that inspections should gather analyzable data that, where possible, could inform ongoing assessments on the state of manufacturing quality and provide some intelligence about the operations of the firm

● that there should be maximum downstream use of information and inspection data to inform FDA and otherregulators. We are looking in the future to develop inspection reports that will be easily utilized by other regulatory authorities.

● to develop an effective and efficient periodic process for preapproval and surveillance inspections. The goal isto increase the efficiency and effectiveness of inspections.

● to develop standards for consistently gauging and grading the state of quality as observed by the investigator

● to develop a standardized inspection report – something that can be easily captured and does not involve areal long narrative account of what happened during the course of the inspection

● that inspections represent a significant amount of human and financial resources. So we are looking tomaximize the return on that investment – to do the best possible inspection.

These activities encompass the preparation prior to the inspection, the execution of the inspection, the capturing of the information in an inspection report, as well as the inspection follow-up.




NIPP Goals and Approach

The goal for NIPP is to develop a new paradigm for inspections and reports that will advance pharmaceutical quality by:

● providing a risk-based and rule-based process during the course of the assessment that uses expert questions

● measuring and describing the state of quality in the inspected facility

● using analyzable assessments – semi-quantitative scoring that can track and improve performance

● coming up with some type of numerical score that will represent each one of the elements that are beingassessed during the course of the inspection

● recognizing and rewarding positive behaviors in cases where facilities exceed basic compliance. Again, it isnot just about finding deficiencies during the course of the inspection, but also determining, describing, and recognizing positive behaviors within the site.

The current approach that we have developed does include the three objectives for the preapproval inspection program. Those objectives are: ● readiness for commercial manufacturing ● application integrity, and ● conformance to application commitments.

On the surveillance side, we are utilizing the six-discipline approach that has been in place. But in addition we are adding some other standardized elements that relate to quality culture – some of the ideas that are embodied in ICH Q10, for example.

We are defining performance levels, including levels that exceed basic compliance. We are including analyzable assessments. Some of that quantitative scoring that will track performance of that particular company from inspection to inspection and between different inspections. So we are looking to create a measuring system that can track performance over time.

We want to provide for a semi-automated production of inspection reports with a fully-searchable format. And that is something that we are doing right now. We are using automated tools to help facilitate the generation of the inspection reports.

Components of NIPP

So, what is the inspection protocol itself?

It is basically a document that optimizes an approach to performing the inspection. It has ratable elements. And these elements are particular items to be covered during the course of the inspection. What we have done is we interviewed a series of experts, and they have shared some of their best practices with us. We have taken those things that are most important to cover during the course of the inspection and we have distilled those down to a list of elements that will be covered during the course of the inspection. Basically, this is the foundation of the protocol.

We have a short narrative of each ratable element – a short description of what is supposed to be covered during the course of the inspection. We have a list of possible areas of coverage. These are just suggestions for the investigators – some examples of what to cover with that particular system. What are some things that are commonly covered?

We have example questions that guide the investigator to the desired areas of coverage.

Lastly, we have example ratings. We thought through a variety of real-life situations to develop the numeric scores to assess the level of quality for that particular site, for that particular system. We are using these to train our investigators to try and calibrate the numeric scoring system that we are using to cover these particular elements.


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As I said, we have defined a number of different performance levels. These levels are used to describe each and every element that is covered during the course of the inspection. They describe the level of performance. There is a level that describes meeting basic performance. There are a number of levels both above and below basic performance. It describes the degree of failure on the negative end and the degree of success on the positive end.

These scores are applied to each element. When the investigator goes through and performs the inspection, they are assigning a particular numeric score to each element that has been covered. Afterword what we can do is aggregate these scores for a particular system. For the quality system, for example, the scores for all of the quality system elements can be aggregated into one single score.

Performance is determined by GMP compliance or violations of GMP compliance, product impact, and readiness for manufacturing in the case of preapproval inspections, and so forth.

Performance levels are harmonized between the preapproval and surveillance programs. We have a preapproval inspection protocol and a surveillance inspection protocol. We have levels of performance that are defined. And these levels of performance are common between the two different inspection protocols. The only difference is that for a PAI we focus on confidence in commercial manufacturing. Obviously since the firm has a pending application, the paradigm is slightly different for a PAI. But essentially they are very similar grading systems.

What we do is we gain knowledge from multiple observations and answered questions. One thing to point out is that there are still going to be inspectional observations during the course of the inspection. The assessment that is being done is in addition to what is normally being done. So the investigator is finding GMP violations. But they are also describing an assessment of each and every system that is being covered. The 483 observations can relate to the score that is received for those particular elements. But they are not necessarily cause and effect – they are related, but they are not necessarily linked.

What we are hoping to do over time is to build up a library of examples of these types of observations. We are in the very early stages right now of this inspection protocol. But as we gain experience when we perform more of these inspections, we are going to capture examples – ratings from different kinds of elements. When we build up a library, what that is going to do is to serve to calibrate each individual investigator’s scores of that particular element. We hope that over time we are going have a greater amount of consensus for scores for each of the elements that are covered during inspections.

Inspection Questionnaire

We have a number of questions that are associated with each one of these elements. As the investigator is performing the inspection, they are using the questions as references to help guide their inspection, and also to help consider the assessment of that particular element.

There are two purposes of the questions. One is to capture information – they ask questions and complete some of the information in the protocol. So it is a means of capturing information about what transpired during the course of the inspection.

The questions are also used to frame the topic for the investigator. So the questions help guide them to drive the inspection in a particular area.

The questions focus on the presence or absence of particular practices at the company. But they also focus on the adequacy of the practices. They focus on observable objective conditions.

We have a number of mandatory and optional elements. We have identified them on a risk basis. For the mandatory elements, these must be covered and are prioritized throughout the course of the inspection.

Use of the questions not only facilitates the inspection process but also subsequent report generation. As the


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investigator collects this information during the course of the inspection, it is going to aid in generating the inspection

report.

NIPP Pilot Status

What is the status of the NIPP pilot? We initiated Phase I of the pilot. We have one ongoing for preapproval inspections and another for surveillance inspections. We have had ten inspections under each protocol. For the preapproval inspections, we are completing the last inspection now. For the surveillance inspections, they will be done very shortly, probably within a month.

It includes training investigators on how to use the inspection protocol. This is a very different manner of conducting the inspections. So we did focus a lot on training and socializing the investigators on the use of the new inspection protocol.

We focused on sterile drug inspections. They were considered to be the highest risk. All of the inspections that have been done focused on sterile products produced by aseptic processing.

The purpose of Phase I of this pilot is to explore feasibility. It is basically to test the concept of operations: Is this something that can be performed by investigators? Do they readily understand it? Do they feel like they are capable of rendering these assessments of each and every element within the inspection protocol? Basically we are trying to determine if it is feasible to use this on a much wider scale.

The inspection protocols are used only for evaluation. They are not used to determine the outcome of the inspection. During the pilot phase, the investigators are using the protocol, they are generating information, but this information is not captured in the inspection report. And it does not drive the ultimate decision making for these inspections.

In other words, if they are performing a preapproval inspection, they are collecting the data, but it is not going to determine the outcome of the preapproval inspection. We wanted to keep the normal inspection process and its assessment separate so that we can pilot and refine these instruments. We did not want to have inspection protocols that are in development influence the course of the inspection outcome. And the same holds true for the surveillance inspection pilot.

What are the preliminary results? We have received some very positive feedback from investigators. We have been pleasantly surprised. A lot of the investigators have said that they really enjoy using the inspection protocol. They think that it is really helpful to guide the course of their inspection. We have had investigators say that they want to use this on an ongoing basis for inspections that are not part of the pilot. They feel that it is a really useful tool to guide their inspections. We have been very happy with the outcome of the pilot.

We are still in the data gathering phase. We are looking to receive formal, written feedback from all of the investigators as well as scores based on their inspections. When we receive the feedback, we are going to aggregate all of the data, look at the outcomes, look at the feedback from the investigators, and try to refine the tool to the extent possible to prepare for the next phase of the inspection protocol project.

What we hope to do starting early next year is pilot Phase II of the project. We are going to expand it to a much larger number of inspections based on the feedback that we have received and on the refined inspection protocol.

The purpose of Phase II is to determine whether there can be consistent scores among different investigators. We want to try to ascertain whether two different investigators can assess the same elements and come up with a similar or the same score. We are still quite a ways away from full implementation. But we are making progress on the pilot.

Next Steps

What are the next steps for NIPP? The inspection process and work products focus on consistently measuring and


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describing the state of quality in the inspected facility. These protocols are all about an objective measurement of the systems that exist within the company that is being inspected. We want to use these analyzable assessments to track and to drive improvement within the company. That is what we are looking to assess.

We want to collect examples of assessments at different performance levels. As I said, we are developing a library. As we perform more of these inspections, we are going to have more information. This information will feed into the database where we have examples of practices that represent different levels of performance.

Some of these inspections are going to identify manufacturing excellence. So that is very much a part of this inspection protocol project. As I said earlier, we do not just want to capture the violations and problems within the company being inspected, but also to recognize and reward examples of positive behavior. We wish to collect this information and identify companies that have practices and systems that exceed basic compliance.

In the future, knowledge from inspections will inform decision making, possibly including site selection. So we may determine what facilities to inspect based on results of the inspection protocols. We may also develop outreach and industry training based on results that we find.

Discussion of future state includes the possibility of sharing scores with the inspected facility to create incentives for quality improvements. This is something that may be down the road. We are a ways from doing this right now. But essentially the long-term goal is to provide this feedback directly to the company that is being inspected about the elements that are being covered, about the levels of performance that we have assessed, and to share this with them in the hope of driving improvement. This is the ultimate goal.

Expected Outcomes – FDA

What are the expected outcomes for FDA?

We hope to maximize the value of the time and resources spent on inspections. We hope to make our inspections more efficient and more effective through the use of this inspectional approach.

We want to provide more consistent inspectional coverage. We want to ensure that multiple inspections have the same breadth and depth of coverage. This is a means of providing consistency in our inspections.

We want to facilitate faster and more consistent review of inspection reports. As I mentioned, our inspection reports right now are in narrative format. And although they have a general structure, they are difficult to analyze unless you are very familiar with the inspection report or you performed the inspection yourself. We are hoping to develop and structure these in such a way that someone can more easily ascertain the level of manufacturing quality that exists in the company without doing an extreme, deep dive into the inspection report.

We hope to provide easily analyzable inspection data for trending, both within and between sites. So as we collect this information from inspections, we want to do comparisons over time. Is the firm improving its state of compliance, or are they declining? And we wish to compare multiple facilities so that we can compare one state of compliance at one facility versus the state of compliance at another facility. Right now that is difficult to with the narrative form of the inspection report. Over time we hope to improve our capability to do that.

We hope to have a tool to help determine future inspection frequency. If we have a company that has been exceeding basic compliance and going above and beyond what they need to do, that company may get inspected at a lesser frequency. Whereas if we find recurrent problems at a particular facility, that facility may get inspected more often.

The goal is ultimately to have more consistent enforcement actions. Since we have more quantifiable, measurable data, we are going to develop our expectations with more level of detail about the level of compliance and what warrants an enforcement action. We hope that it will help drive more consistency in our process.

More structured data will allow for easier trending. Of course, if we have more standardized formats of the data, we


WWW.IPQPUBS.COMSEPTEMBER 2015 1�


will be able to provide trending over time for a particular facility and between facilities.

Expected Outcomes – Industry

What are the expected outcomes for industry?

We hope to provide more consistent inspectional coverage and observations. Really this is about driving consistency in our inspection process – ensuring that investigators are performing the same inspection over time and that the same types of inspections are performed by different investigators.

We are trying to develop a level of consistency but still allow for flexibility on the part of investigators. When they find problems we are certainly not going to constrain them in any way. I think the expected outcome from industry will be that there will be more certainty about the different elements that are covered during the course of an inspection.

Over time, it is going to help provide clarity in expectations. What are FDA’s expectations for industry practices? I think that will become clearer as we adopt this new approach for our inspections.

We hope to provide a benefit – namely fewer inspections for firms with high levels of compliance. Companies that adopt above and beyond the basic expectations for GMP compliance will benefit from fewer inspections.

We want to recognize and reward positive behaviors in cases where we see beyond basic compliance.

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Phased implementation, reporting burden, and the nuances of site versus product reporting were among the focal points of the comments by the various associations appearing at the public meeting held by FDA on August 24 to capture industry’s initial feedback on the agency’s quality metrics draft guidance.

Also drawing industry attention at the meeting were the statutory authority for the reporting expectations delineated in the draft guidance and how they apply to active pharmaceutical ingredient (API) suppliers and contractors.

The draft guidance and a substantive Federal Register notice accompanying it were released by FDA in late July (see IPQ “Monthly Update” July-August 2015, pp. 3-10).

In line with industry requests voiced at the meeting for more time to digest the draft guidance and to consider the specific questions on which the agency had asked for more input (ibid.), a follow-up Federal Register notice was issued on August 27 providing for a 60-day extension on the written comment period to November 27, 2015. [A link to the notice is provided on the next page.]

ll of the industry associations appearing at the August hearing indicated that they would be fleshing out the concerns and suggestions they were voicing at the hearing in their subsequent written comments. [A list of the names and affiliations of the FDA and association representatives making comments, in order of their appearance, is provided on the next page.]

Moderating the meeting was Center for Drug Evaluation and Research (CDER) Office of Pharmaceutical Quality (OPQ) Office of Policy for Pharmaceutical Quality (OPPQ) Acting Deputy Director Brian Hasselbalch. An overview of how the metrics initiative fits into the larger effort by the agency to modernize its quality regulatory processes and better assure patient access was provided by CDER Director Janet Woodcock, followed by more detailed discussions of the metrics initiative and guidance by OPPQ Acting Director Ashley Boam and CDER Office of Strategic Programs Senior Advisor Ron Fitzmartin.

Fitzmartin focused on the technical specifications and data standard details set out in the draft guidance associated with the electronic submission of metric data. He explained that a technical conformance guide (TCG) has been developed by

FDA as a user guide to the technical specifications, which is currently awaiting clearance.

The TCG will include a set of validation rules that manufacturers will need to run prior to submission of their data to make sure no transmission errors arise, along with the data exchange formats and an explanation of how the data will be transported to the agency through the electronic gateway. Stakeholder input will be sought on the document once posted, Fitzmartin stressed.

FDA Estimate of Reporting Burden Questioned

The size of the reporting burden and what could be done to reduce it was another area of concern receiving attention through the course of the meeting.

Both ISPE and GPHA found the paperwork reduction act projections outlined by FDA in the Federal Register announcement of the draft guidance to be “significantly underestimated.” They called for reassessing them to take account of the actual metrics processes required to meet the reporting requirements, including the additional review and retention of data to support verification during inspection, and the anticipated costs for firms to adjust their internal IT systems.

ISPE cited its Wave 1 industry pilot experience in support of its comments on the metrics reporting burden and noted that the Wave 2 pilot is currently gathering additional case study examples to provide further clarification. [For more details on the ISPE quality metrics initiative see IPQ “Monthly Update” July-August 2015, pp. 11-27.]

In response to an FDA panel question on the Wave 1 findings, Hagerty explained that ISPE asked firms to indicate the number of hours involved in collecting and reporting the data asked for in the pilot – a broader metrics set than FDA is requesting in the draft guidance.

The pilot participants reported a “large range of burden and time” involved, she said. “It is one thing to look at that data for the internal systems. It is a second thing to take that data and report it. There may be adjustments needed to IT systems. There will be secondary levels of review required for that. And so that is why there is a very significant difference from the industry side compared to what we see in the Federal Register notice.”

Phased Implementation, Reporting Burden Among Industry Focal Points in Initial Feedback on FDA’s Quality Metrics Draft Guidance







Relevant to both the phased implementation and reporting burden issues is the on-going debate relating to site versus product reporting.

The majority of the associations presenting at the public meeting indicated a preference to commence the program with a site-based reporting model. The contention was made that this model better supports a phased start-up as it reflects the current industry metrics collection and reporting practices and is therefore deemed to be less burdensome.

Is Further Statutory Support Needed?

PhRMA and GPHA both voiced concern that FDA may lack the legal authority to require manufacturers to develop and submit the quality metrics data requested in the draft guidance that are not spelled out as a requirement in the current GMP regulations.

If FDA seeks to implement a mandatory reporting program, PhRMA maintained that “the agency should promulgate new requirements through binding rulemaking.”

GPhA stated that although the FDA Science & Innovation Act (FDASIA) grants authority to FDA to request metrics in advance of inspections, in its opinion this is limited to inspection of records that companies already keep, not to

the generation of the new metrics records that FDA is now requesting.

Furthermore, GPhA pointed out that information about contractor and supplier performance may not be currently available as specified – presenting product-based supply chain reporting challenges for their members.

Maintaining that the guidance is too prescriptive in nature and imposes “binding and rigid rules” that fail to provide practical alternatives to comply, GPHA’s Gaugh raised concerns relating to the consequences arising from failure to report information.

The draft guidance indicates that failure to report could be deemed by FDA as the equivalent to refusing an inspection and may render products to be considered “adulterated.” Making this equation, Gaugh asserted, was effectively imposing “de-facto increased inspection penalties.”

During the Q&A following his talk, the FDA panel probed into some of the concerns raised by GPHA, including: where, in particular, the metrics reporting burden was “underestimated” by the agency; what data is not currently expected to be collected; and where the draft guidance proposed “unreasonable” expectations.

The panel also asked that GPHA further clarify in its written

FDA August �� Quality Metrics Public Meeting Agenda

The following is a list of the names and affiliations of the FDA and association representatives making com-ments at the Aug. 24 public meeting, held at the agency’s White Oak headquarters. The list is in order of appearance.

FDA’s Opening Remarks

● Moderator: Brian Hasselbalch, Acting Deputy Director, Office of Policy for Pharmaceutical Quality (OPPQ), Office ofPharmaceutical Quality (OPQ), CDER● Janet Woodcock, Director, CDER and Acting Director, OPQ● Ashley Boam, Acting Director, OPPQ, OPQ, CDER● Ron Fitzmartin, Senior Advisor, Office of Strategic Programs, CDER

Trade Association Presentations

● Diane Hagerty, International Society for Pharmaceutical Engineering (ISPE)

● John Punzi, Consumer Healthcare Products Association (CHPA)● Richard Johnson, Parenteral Drug Association (PDA)● Camille Jackson, Pharmaceutical Research and Manufacturers of America (PhRMA)● David Gaugh, Generic Pharmaceutical Association (GPhA)● Priscilla Zawislak, International Pharmaceutical Excipients Council of the Americas (IPEC-Americas)● Alan Nicholls, Bulk Pharmaceuticals Task Force (BPTF), Society of Chemical Manufacturers and Affiliates (SOCMA)

Open Public Comment, Closing Remarks and Adjournment

● Russell Wesdyk, Acting Director, Office of Surveillance, OPQ, CDER


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comments what the incremental, risk-based approach it was recommending would look like and where it would start.

Gaugh responded that GPHA is currently reviewing the issues raised by the panel and would address them further in the written comments.

Voluntary Reporting During Phase In Proposed

Making metrics reporting voluntary – at least in the initial stages of implementing the program – was proposed by GPHA and ISPE as a pathway to work through the regulatory and technical concerns involved.

In recommending a “phased introduction” of the program, ISPE suggested that one of the ways FDA could consider would be starting with “a voluntary reporting approach during the initial learning period in order to help companies get up to speed with reporting the data….as we believe that this would be an important opportunity for the FDA to learn based on the volume of data that may be coming into your organization.”

OPPQ Acting Director Boam asked Hagerty after her prepared remarks if the phased in approach ISPE was describing wouldn’t involve a ”missed opportunity to get a sense for what the metrics might look like over a broad swathe of the industry.”

Would it be more likely, Boam querried, “to get reports from those firms that have participated in your pilot or have been doing this a little longer and have more familiarity with it, and not really get a sense with the metrics themselves, the burden, the issues in terms of data presentations and what the definitions might be from those who are both very familiar and those who might not have been as familiar with this program?”

ISPE does recognize that with a voluntary approach, “you might not get that representative sample that you are looking for across the industry,” Hagerty responded. The advantage of starting with a voluntary program, on the other hand, she suggested, is that it could: “help get more awareness across the industry and get people reporting, even within firms; it would allow for more flexibility for the amount of data that firms are going to have to be providing; and it could allow for a more phased approach for firms.”

In discussing a voluntary or other type of phased-in approach, the ISPE team did give consideration to the possibility of a sampling process that would give more representation initially across industry, Hagerty noted.

A related issue, she pointed out, would be the volume of data that will be coming into FDA and how it would be used, and how that may shape both the industry and FDA reporting experience. She reiterated the ISPE mantra of focusing on “starting small, learning, and evolving.”

Expectations on API Suppliers and CMOs of Concern

Concerns around how the reporting expectations would play out for API suppliers and contract manufacturers were focal points of the comments by the Bulk Pharmaceuticals Task Force (BPTF) and the Pharma and Biopharma Outsourcing Association (PBOA), respectively.

BPTF operates under the umbrella of the Society of Chemical Manufacturers and Affiliates (SOCMA) and represents manufacturers of APIs, intermediates and excipients. Speaking on behalf of BPTF at the FDA meeting was Copperhead Commercial & Reg Affairs Senior Advisor Alan Nicholls, who serves as its current chair.

PBOA was established in 2014 as a non-profit trade group to represent contract manufacturers. Commenting during the “open mic” session of the FDA meeting for PBOA was its president, Gil Roth.

Nichols noted that BPTF members were not clear on how to interpret the draft regarding responsibility for the reporting process between API and finished dosage form (FDF) manufacturers and suggested the need for FDA to provide greater clarity in its directions and related definitions.

Reporting by the FDF manufacturer could be problematic in the case of API purchased by multiple customers, he pointed out. An API manufacturer would potentially have to segregate data for lots supplied to each customer in order to prevent double counting.

Nicholls noted that one of the speakers in the FDA webinar that accompanied the draft’s release had commented that a holder of an API drug master file may submit the reports directly to the agency and list each product that uses the API. BPTF, he said, would support the inclusion of this option in the final guidance.

A related issue would be whether the data should include lots of an API that are exported and not used in an FDA “covered drug product.” Nichols noted that trying to tease out that data would present challenges, given the normal coupling that takes place.




Roth also pointed to “a bit of ambiguity” in the draft guidance on whether contract manufacturers would be responsible for: ● reporting the metrics information directly to FDA, rather than the license/contract holders that they are working with, and ● collecting information from API suppliers andother contractors that are involved in making the drug.

Having to do so, the PBOA president stressed, “could create a very significant burden on CMO’s, especially given the adulteration aspect of not complying.”

The guidance defines “covered establishments” as extending to contract labs, sterilizers, contract packagers and other establishments engaged in the manufacture of the product. The question of concern to the CMO community, Roth indicated, is who has the “reporting” responsibility.

GPHA offered a different perspective in commenting on the issue. The generics association suggested that FDA should request metrics directly from contractors, in keeping with their direct regulatory relationship with them, and not request the application/contract holders to gather and compile data from contractors, given that they are not parties to contractor FDA inspections.

Following the GPHA comments, an FDA panelist referenced the divergent opinions being expressed on the issue, pointing to concern whether there would be “comfort on the part of the application holder, for example, if data was coming directly from the contract manufacturer without their oversight.”

Gaugh acknowledged that the point “is a good one” and had come up in the GPHA discussions, adding that the association’s quality technical group would be discussing the issue as part of its all-day meeting on the draft the next day.

The concern is two-sided, Gaugh pointed out. If the data comes to the application holder, “are we interpreting what they have done correctly, accurately, and appropriately?” And conversely, if the contract manufacturer reports it “on their own, without including us, are they providing the information and data as we understand it, and as we see it through our contracting process?” GPHA, he said, “thinks there needs to be a back-and-forth collaboration there.”

In response to the questions raised by Nicholls and Roth on the reporting responsibilities, Office of Surveillance Acting Director Russ Wesdyk

explained that the intent was that separate reports would come in from the API and finished dosage form manufacturers, with the API suppliers responsible for reporting their data.

In the outsourcing context, he said, the idea was that the application holder/sponsor would be collecting the data and doing the reporting, reflecting the responsibility of its quality unit oversight responsibility for the various outsourcing sites.

Wesdyk affirmed that the agency would be considering the dialogue at the meeting related to the reporting responsi-bilities and the intellectual property considerations.

CDER’s Tara Gooen pointed out the challenge the agency has in trying to come up with language that would address non-application products as well in delineating the repor-ting expectations.

A consideration, she commented, is that the reporting establishment have a business relationship with all the contracting facilities associated with the manufacture of the product, and not necessitate the CMOs reaching out to, for example, contract labs, with whom they may not have a direct contracting relationship.

Following the ISPE presentation, Gooen asked Hagerty to comment further on the reporting burden on contract manufacturers and labs that she had mentioned.

Reporting by site would involve the contract manufacturer in the reporting process, Hagerty responded, raising issues for the CMO as well as for the contract giver. Since the CMO is not the authorization holder, the concern is “what level of review they may need to go through with the firms that they are contracted with in order to report that data,” she explained.

Atypical Actives, Excipient Coverage Addressed by IPEC

The issues around supply chain tracking and reporting responsibilities, as well as the scope of the initial FDA program, also surfaced in a different context in the comments made by the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) – a trade association comprised of excipient manufacturers, distributers, and pharmaceutical industry users.

Presenting for IPEC-Americas, Ashland Global Regulatory Affairs Manager Priscilla Zawislak noted that some


SEPTEMBER 2015 1� ......... ....


excipients are used as “atypical actives” in both over-the-counter (OTC) and prescription drugs, often without the excipient manufacturers knowledge. Since the proposed guidance includes reporting requirements for APIs, the association, she explained, would like to understand how this might impact excipients that are used as atypical actives and where the reporting responsibilities lie.

In focus for IPEC-Americas was question four of the nine questions on which FDA asked for input, in particular, in its Federal Register announcement of the draft’s release and the August meeting (see IPQ “Monthly Update” July-August, pp. 3-10). Question four asks if the agency “should explore collecting metrics from high-risk excipient producers, and if so, which excipients should be considered high-risk and what metrics should apply?”

[Editor’s Note: The comments made by the various associations at the FDA meeting related to each of the nine questions posed by the agency are listed below.]

Zawislak pointed out that there is currently no definition for “high risk” excipients. It is the position of IPEC-Americas, she explained, that the risks relevant to the guidance are not related to the manufacture of the excipient but to their use in high risk products and/or applications.

Quality metrics, including those proposed by FDA in the guidance, are based on the manufacturing process. However, Zawislak noted, most of the issues associated with excipients being labelled as “high risk” have been related to supply chain integrity and economically motivated adulteration and “are typically not related to the manufacturing process.”

The use of excipients in a variety of applications that have varying risk profiles “makes it nearly impossible to assess whether the excipient should be considered high risk or not relative to quality metrics for the manufacturing process.”

IPEC-Americas overall recommendation was that the agency should finalize the guidance and resolve the outstanding questions for drug products and drug substances before considering applying quality metrics to excipients.

Transparency Urged

Several of the industry associations encouraged FDA transparency around how the data will be used to support decision-making.

ISPE and PhRMA, for example, requested more feedback from the agency on how the proposed quality metric data

will enable the prediction of drug shortages and how it will link to the determination of risk-based inspection scheduling and post-approval change reporting.

Communicating the benefits arising from the reporting program was high on ISPE’s agenda. Hagerty commented that evidence of early benefits are most likely to be demonstrated by focusing on the relationship between site performance data and risk-based inspection frequency.

ISPE pointed to the need for transparency around: ● how the data will be used – for example, regarding public disclosure, trending, context comments, or calculation of an aggregate “college board type” score for site or company comparisons ● the algorithms used for inspection scheduling and drug shortages ● the potential safe harbor period, and ● if/how the data submitted has resulted in reduced inspection frequency or post-approval reporting.

After the prepared comments, moderator Hasselbalch probed into the ISPE request for transparency on FDA’s algorithms for inspection scheduling.

“For a decade now we have been using an algorithm to rank sites in terms of priority, greatest to least. Those have not been made public, protected by a non-disclosure rule. Can you explain why you think it is important for the industry to know what those algorithms are?” the CDER official asked.

Hagerty responded by emphasizing the “spirit of transparency with which this program is moving forward – to try to really encourage and show good faith with that”so firms understand how their data is being used and to reinforce good behavior and the data reporting process.

She agreed with Hasselbalch’s rephrasing of the thrust of her recommendation as “understanding firm by firm how the data influenced our inspection frequency rather than some general announcement on the algorithm or algorithms.”

The public disclosure and the public transparency overall is another question, the ISPE metrics team lead concurred. “I think the important thing is also individual communications to firms, so that they are understanding what their data set may be” in context, including that of the broader benchmarking data.

Rejecting Lots May Be a Plus

During the “open mic” session, industry consultant Trevor Deeks echoed a theme that has been prominent in CDER






Director Woodcock’s and Office of Surveillance Acting Director Wesdyk’s discussion of the FDA metrics initiative – the need to be very mindful of any unintended consequences of the collection process that would be counterproductive to the initiative’s goals.

Deeks urged caution on how the data is interpreted, citing rejected lots as a case in point.

“Rejected lots do not present a risk to the patient because they are not going to get to the patient,” he stressed. “A rejected lot is an indication that the quality system and the quality unit, has actually, in some respects, done its job properly.”

“What we need to be worried about,” he suggested, “is the lots that should have been rejected but were not, and we usually see those as product recalls. That is a measure, a number, that we can possibly look at.”

In turn, an increase in rejected lots “may a good thing, not a bad thing,” Deeks pointed out. “because that would indicate that the quality unit the company is putting in place measures to address the problems that weren’t be picked up previously.”

In concluding her opening remarks at the August meeting, Woodcock made clear that the agency is fully aware of these data interpretation challenges and “has to get a lot of experience under our belt before we understand, even at a very simple level, what these metrics mean.”

As Russ Wesdyk has pointed out to her many times, she said, the indicators may reflect the ability of firms to find and address problems. “For example, if you do some recalls because you are being very careful, you would not want to penalize people for that. So we have to make sure that we do not have unintended consequences from operating these metrics.”

Woodcock stressed that the agency plans to “have a time period once we start collecting [the data] during which we will be able to process what they mean and also the industry will be able to learn.” The metrics effort, in turn, she pointed out, is part of the agency’s effort to move in the post-market period – “a time when all the patients are exposed to all the drugs” – toward “an objective and well-understood and reliable system for understanding the quality of pharmaceuticals.”

Sanofi U.S. Quality Liaison/Global Quality VP Edwin Rivera-Martinez, a former CDER compliance

official with API policy setting responsibilities including helping develop ICH Q7A, brought attention during the open public session to question six of the nine questions on which the agency had requested feedback, addressing the viability of the “right-first-time” metric.

The agency asked if right first time should be added to the list of the metrics being examined, and if so “should the definition be a rework/reprocessing rate or a measure of lots manufactured without processing deviations?”

While the meaning of reprocessing and reworking is relatively clear in the API context, it is “not clearly defined” for finished dosage form manufacturing, Rivera stressed, and the terms wouldn’t be appropriate to support a right-first-time metric in the FDF context.

“My experience both in FDA and industry has shown that reprocessing/reworking of finished dosage forms is really a very rare event,” he commented, “and usually causes quite a bit of consternation among regulatory inspectors.” He has seen companies take units and relabel or repackage them and call that, inappropriately, a rework or reprocessing.

CDER Looks Forward To Shared Learning and Continued Dialogue

Offering the agency’s appreciation for the level of stakeholder involvement throughout the last two years in CDER’s outreach effort on the metrics initiative at the conclusion of the meeting, OPQ Office of Surveillance Russ Wesdyk acknowledged the role this feedback has played in reaching the current position.

He stressed that active engagement will continue to remain important in the initial implementation learning phase and that the FDA metrics team is looking forward to the submissions on the public docket.

Among the key messages he heard during the meeting, Wesdyk summarized, was the need to take a phased or risk-based implementation approach, to provide more transparency about how the data will be used, and to continue the dialogue.

FDA will also be carefully considering the questions raised about definitions for specific metrics and how that data will be correlated, he said, noting that further national and international outreach prior to publication of the final guidance is planned.


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Wesdyk indicated that a final guidance is not expected in 2015, and that the agency plans to issue an update to the guidance about six months after the first set of metrics are submitted and utilized by the agency that will reflect the initial learnings.

The initial learning period will also be used to study the relationships that given metrics have with potential signals and outcomes. Wesdyk stressed that the metrics will not be used in isolation to make regulatory decisions and

confirmed FDA’s determination to minimize the burden of this program.

The metrics program is intended to assist FDA in assessing supply chain and disruption threats, he reiterated in closing. Information from manufacturers of “where they are and how they are” is needed to advance the agency’s cause of “insuring that patients have high-quality, life-saving products.”

COMMENTS AT AUGUST MEETING RELATED TO NINE QUESTIONS POSED BY FDA

The following are comments/recommendations made at the FDA August meeting related to the nine ques-tions on which FDA specifically asked for input. ISPE and PDA went through the questions in a more linear fashion, while other associations may not have specifically referenced the question in making the related comment.

(1) Are there other objective metrics that FDA should request in advance of or in lieu of an inspection that FDA should collect to improve our understanding of products and establishments for purposes of more informed, risk-based inspection scheduling and identification of potential product shortages?

ISPE: Not at this time. The proposed metrics, with the exception of annual product review (APR) on time, represent insightful metrics that can be most easily standardized across industry. Start small and expand if needed as part of a phased introduction of the metrics program.GPHA: Inspections are of records companies keep already, and the authority is missing to require manufacturers to generate new records for investigators or for filing in advance.PDA: Quality culture is critical, but not an easy to report in metric form and better to assess on site in practice.CHPA: Regarding the optional metrics proposed by FDA, proposes sharing with senior management rather than “rubber stamping” the review and approval of lot release as more important – an area that is best addressed during inspections rather than through reporting.

(�) Are the definitions of the metrics and associated data requests selected adequate and clear?

ISPE: Provide more clarity on requested data to ensure consistency in interpretation across industry, such as: ● invalidated OOS rate – nonstandard definition appearing to include a double normalization ● specification-related rejects – since the term “specification” can have very broad interpretation, request examples to ensure full understanding ofintent ● finished dosage form ● establishment ● lot, and ● product quality complaints.CPHA: Clarify and refine data reported.GPHA: Clarify metrics definitions using industry feedback. Allow for metrics context to be included to prevent misinterpretation.PhRMA: Develop mechanisms for technical support and stakeholder engagement to ensure consistency of interpretation of the definitions of the data and metrics requested. Engage with technical experts in data analytics to establish correlations between reported metrics and associated analyses of effectiveness of the quality metric program approach.BPTF: Provide greater clarity and examples for reporting directives and definitions in the guidance – in particular, the definitions of ‘lot attempted’ and ‘lot release test.’

(�) Are the metrics requested from each business segment/type clear and appropriate?

ISPE: Clarity is needed on definitions of business segments and/or examples to be included, such as: ● finished dosage form ● API – penultimate only? Include biological drug substance? ● non-registered establishments, and ●


WWW.IPQPUBS.COMSEPTEMBER 2015 �0


atypical actives (some actives are excipients in other environments; eg., calcium antacids).

CPHA: Quality metrics implementation should begin with high-risk facilities/products.PhRMA: Strive to integrate all FDA surveillance activities and indicators through collaboration between CDER, CBER, CDRH, and ORA. Continue dialogue with stakeholders, including PhRMA and our member companies, on the technical and operability aspects of the program as more specific details are announced and implemented to assure data reporting and analysis mechanisms that are scientifically robust and minimize the resource burden to both industry and FDA.GPHA: Request metrics directly from contractors, in keeping with their direct regulatory relationship with them, and not require application holders to gather and compile data from contractors, given that contract holders are not parties to contractor FDA inspections.BPTF: Clarify reporting responsibilities between FDF sponsors and API DMF holders. Allow for direct reporting by API firm. BPOA: Clarify reporting responsibilities between license/contract holders and contract manufacturers. Direct reporting to FDA and having to collect information from API suppliers and other contractors could place significant burden on CMOs.

(�) Should the agency explore collecting metrics from high-risk excipient producers, and if so, which excipients should be considered high-risk and what metrics should apply?

ISPE: Not at this time – the proposed program is consistent with the objective of “start small, learn and evolve.”The impact of critical excipients on product quality outcomes is best managed directly by manufacturers and can be detected through some of the proposed metrics such as lot acceptance rate.PDA: Dialogue further with the industry about developing a common definition and applying the appropriate metrics to these sites.IPEC: Finalize guidance and resolve unanswered questions for drug products/drug substances before considering whether to apply quality metrics for any excipients. There is currently no definition for high-risk excipients. Risks that might be considered for the metrics guidance are not in the manufacture of the excipient, but rather their use in high-risk products and/or applications.Some excipients are used as “atypical” actives in both OTC and Rx and drugs, often without the excipient manufacturer’s knowledge. Explain how proposed guidance would impact excipients that may be used as “atypical actives.”

(�) Should the Agency explore collecting metrics from the medical gas manufacturing industry?

ISPE: The proposed program is sufficiently extensive as a start. Expand program later if needed.The impact of medical gas on product quality outcomes is best managed directly by manufacturers and can be detected through some of the proposed metrics such as lot acceptance rate

(�) Should the agency add the “right first time” metric, and if so, should the definition be a rework/reprocessing rate or a measure of lots manufactured without processing deviations?

ISPE: Not at this time – the proposed program is consistent with the objective of “start small, learn and evolve.” The experience in the ISPE Wave 1 pilot indicated that it is a challenge to get to a standardized definition for this metric across industry.“Right first time” is an appropriate metric for companies and sites to develop and use to drive their own continual improvement activities.PDA: A good future metric to consider. The feedback at its 2014 PDA Quality Metric Conference was to start with a rework/reprocessing rate and develop a common definition/understanding of which deviations are valuable to define “right first time” metric.SANOFI’s RIVERA: Rework/reprocessing is not clearly defined/applicable in the FDF context and not useful in establishing a right-first-time metric for FDFs.


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(�) What data standards/mechanisms would be useful to aid reporting and how should the submissions be structured? [See also responses to question 8 below on product vs. site reporting.]

ISPE: Report data by site, differentiated by product for lot acceptance and invalidated OOS rates. For product quality complaint rate, report by product only. Collecting and analyzing metric data by site is current practice for industry, and site risk-based inspection frequency planning is best accomplished by reporting data by site (see also question #8 below).Trending of a site’s performance is more important than comparison of single values in isolation across sites and companies and best manages the variability that could be introduced due to inconsistency in interpretation or reporting expectations.Provide transparency around FDA’s analytics/algorithms.100 word limit for comments may not provide sufficient context for reported data.PDA: Collecting metrics by reporting establishment/product segmented by site would generally provide most valuable data for drug shortage prevention.CPHA: Refine and clarify data reporting. Report at site level, and time to APR cycle. Limited text field can be of substantial value.GPHA: At a minimum, provide the safe-harbor period FDA had communicated prior to the draft guidance in order for companies to prepare for accurate, meaningful metrics reporting. Take an incremental approach. Use pilots(s) to determine effectiveness and allow FDA better understanding of how to utilize data.Infrastructure and systems to support metrics reporting externally will require significant, added ongoing cost that must be factored into the burden.PhRMA: Establish data reporting and analysis mechanisms that minimize the resource burden to both industry and FDA.BPTF: Allow a manufacturer to use its current time frame for conducting its APR or PQR as the timeframe for reporting quality metric data.Include a text field for explanation of unusual data or trends.

(�) Are there reporting hurdles to collecting metrics by reporting establishment/product (segmented by site) versus by site (segmented by product), and how can they be overcome?

ISPE: There would be a significant additional burden for industry to report data by product, differentiated by site, as the association’s Wave 1 data suggests (see also question #7 above). Evidence would be required to demonstrate how the proposed quality metric data at a product level differentiated by site with annual reporting frequency enables prediction of drug shortages.Important to show benefit from the reporting program, and early benefits are most likely to be seen by focusing on the relationship between site data and risk-based inspection frequencyCHPA: Report at site level.GPHA: Report metrics on a site basis, instead of product-aggregated.Request metrics directly from contractors, in keeping with their direct regulatory relationship with them, and do not request application holders to gather and compile the contractor data, since the holders are not parties to FDA’s inspections of the contractors (see also question #3 above). PhRMA: Begin with a small number of metrics. Introduce the program in a step-wise fashion. Update the cGMP regulations through rulemaking if it seeks to create a legally binding obligation for a mandatory data collection program. Clarify the agency’s plans for disclosure of quality metrics data.

(�) FDA may consider whether to require the submission of quality metrics on a recurring basis. How frequently should metrics be reported and/or segmented within the reporting period (e.g., annually, semiannually, or quarterly)?

ISPE: Submit annually to FDA. Any additional segmentation beyond annual will add to the reporting burden for firms.Afford flexibility in the report timing to enable firms to align with internally established practices (eg., APR schedule, management review).


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PDA: As per PDA’s Points for Consideration for Quality Metrics, submit annually, segmented quarterly.CHPA: Time reporting to APR cycle.

PhRMA: Establish data reporting and analysis mechanisms that minimize the resource burden to both industry and FDA

BPTF: Allow manufacturer to use its current time frame for conducting its APR or PQR as the timeframe for reporting quality metric data.

ASSOCIATION COMMENTS AT AUGUST FDA QUALITY METRICS MEETINGThe following are the oral comments made by the various associations that appeared at the August 24 meet-ing at FDA headquarters. In order of appearance, the associations and the speakers representing them were the: International Society for Pharmaceutical Engineering - Genentech Quality Systems and Processes VP Diane Hagerty ● Consumer Healthcare Products Association - CHPA Quality Assurance and Technical Affairs Director John Punzi ● Parenteral Drug Association - PDA President Richard Johnson ● Pharmaceutical Re-search and Manufacturers of America - PhRMA Scientific and Regulatory Advocacy Director Camille Jackson ● Generic Pharmaceutical Association - GPhA Science and Regulatory Affairs Senior VP David Gaugh ● In-ternational Pharmaceutical Excipients Council of the Americas - Ashland Global Regulatory Affairs Manager Priscilla Zawislak, and ● Bulk Pharmaceuticals Task Force, Society of Chemical Manufacturers and Affiliates - Copperhead Commercial & Reg Affairs Senior Advisor Alan Nicholls. The moderator for this session, to whom some of the speakers referred, was CDER OPQ OPPQ Acting Director Brian Hasselbach.

ISPE (HAGERTY)

Thank you to the entire FDA organization on behalf of the International Society for Pharmaceutical Engineering. We appreciate the opportunity to participate in the meeting today and provide comments in this public meeting.

Just as an introduction: My name is Diane Hagerty. I am Vice President of quality for Genentech and Roche. And I am really here representing ISPE as one of the many volunteers who are actively engaged in the quality metrics program. We very much appreciate the opportunity to have been actively engaged with FDA over the last three years during the development of this program.

The comments that I am going to be providing today really represent the input from the entire ISPE membership. However, they are largely formed on the basis of the objective experience that we have obtained from the Wave I of the ISPE quality metrics pilot program.

And so on behalf of that program, I also really want to make an acknowledgement and a thank you to all of the companies that have been participating in that effort. Also, just as a few opening comments: The way we have structured our presentation today, given the ten-minute time restriction, is that we are going to be focusing on key messages within the slides I will be presenting. We have already provided to FDA as an appendix to the slide deck specific responses to each of the questions that FDA has answered.

In terms of some of the key messages:

● I think first and foremost one that we have for this program is the importance of starting small, learning, and evolving. And I think that is echoed by what we have heard both from industry as well as the FDA side.

● ISPE certainly supports FDA’s efforts to input a quality metrics program with the intent of really focusing onrisk-based inspection scheduling, and we see that as a near term beneficial opportunity for this program.

● Also it has the potential to provide early indicator and mitigation of drug shortages, which is one that webelieve will perhaps be a longer term benefit. It may take some more time to generate that.


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● We are very much supportive of the FDA’s discussion of the program to help define risk-based principles for reducing post-approval manufacturing change reporting categories. Again, we see that one as one that will probably be a longer term benefit for such a program.

Phased IntroductionAs I stated, ISPE really supports the need for the program to start with a small and targeted approach to enable both industry and FDA to learn and evolve the approach overtime. Along with this, we would recommend that there is a phased introduction of the program.

There could be a number of different ways that the phased introduction could be accomplished:

● For example, it could be initially focused on higher risk facilities or products – for example, medically necessary products with no alternatives. We do recognize that the way the guidance document is written at this point, it is very broad spanning across industry. And we certainly recognize that there are differences from the different types of products that are governed under this, from again medically necessary products all the way to medicated sunscreens. So there may be some opportunity again for a phased approach to the program.

● Another opportunity may be for FDA to start with the focus on the final dosage forms first and defer the API reporting to a later phase of the program.

● We would also like to recommend a consideration for starting with a voluntary reporting during the initial learning period in order to help companies get up to speed with reporting the data as well, as we believe that this would be an important opportunity for the FDA to learn based on the volume of data that may be coming into your organization.

FDA’s Starting Metric SetIn terms of some of the additional comments related to the starting metric set and the overall reporting structure:

ISPE is supportive of starting with three of the proposed metrics: This would be lot acceptance rate as well as the product quality complaints, and the invalidated OOS rate.

I will speak a little bit further about APR on time: We are not recommending that as a starting metric, but rather to defer that as a potential future metric.

In terms of the starting metrics, we would also recommend to have the consideration to report these metrics by site differentiated by product, versus the current proposal of the draft guidance, which is to report by establishment or product differentiated by site.

Also in this case we would recommend to report the product quality complaints at a product level only. In terms of the deferred potential future metrics, one that I have talked about briefly is APR on time. The reason that we have really shifted this metric from the initial starting set to a deferred set really comes in part on the basis of the ISPE Wave 1 pilot. In that pilot we were really trying to focus on which metrics could be correlated to objective performance and outcomes. And in that initial Wave 1 pilot, we did not see correlations of the APR on time.

In addition, and perhaps more importantly, the discussion that we have been hearing really across member companies at this point is the potential concern of the unintended consequence for APR on time, such that firms would focus more on timeliness than they would focus on quality of the information in the APR. And again, we feel that more time may be needed to bring firms up to speed and to have this initial focus – which is focused on the quality of the information in the APR.

With regard to the optional metrics that FDA has proposed related to quality culture, process capability and performance, as well as management engagement, we do recommend that these optional metrics not be reported at




this time, even as optional, but that they be deferred as potential future metrics. Again, part of the basis of this is really as an initial program to help keep focused on a smaller starting set of starting metrics.

I want to move on to starting with reporting by site differentiated by product. We do recognize that this will be a difference in terms of the templates the FDA has provided in the draft guidance document. We believe in those two metrics. So this is lot acceptance rate as well as invalidated OOS rate. It would be helpful to start with site differentiated by product for a couple of reasons: One, right now it is more representative of how the industry is currently gathering this data.

And what we have seen with the templates as proposed is that typically for firms they will report this data as a site, it will require more work at a higher level within the firm, very probably, to reformat that data into a format which is directed by product differentiated by site.

So in order to start with reporting by site differentiated by product, this may help to reduce the burden of the initial reporting program. With this we do recognize that we have had comments, and we do recognize that if we are to start reporting by site differentiated by product this will create complexity for some of the contract manufacturers in the contract labs. So we do recognize that this would be a difference in terms of the templates that FDA has provided in the draft guidance document.

Reporting Burden and TransparencyI want to move on in terms of the key messages related to reporting burden and transparency: One of the things we have identified in terms of the Federal Register notice and some of the burden estimates in the notice, we do believe that those burden estimates are significantly underestimated.

This is on the basis of the data that we gathered in Wave 1 of the pilot. We also currently have case studies ongoing as part of the Wave 2 pilot for ISPE to generate data specific to the metrics that are now proposed in the guidance document.

One of the comments and concerns that we have heard very strongly across the representative companies is really the anticipated costs for review and intention of data to support the program as well as to support the intention that has been stated that FDA would very likely be looking to verify this data upon inspection. So we believe that that is an important piece of the burden that needs further evaluation. For many firms reporting the product differentiated by site represents additional complexity and burden.

And then lastly we believe that it is also very important to have an open communication to understand how the data has resulted in perhaps reduced inspection frequency or post-approval change reporting. Again, we really believe that it is really important to help reinforce approval data so that firms understand what is really leading the post-approval data.

CHPA (PUNZI)

Good morning panel. We appreciate the opportunity to be here to speak today…. My name is John Punzi. I am the Director of Quality Assurance and Technical Affairs at the Consumer Healthcare Products Association. CHPA is the not-for-profit trade association representing the leading manufacturers of over-the-counter medicine. I am making just a few oral comments today, and we plan to submit more detailed written comments by the September deadline.

I want to share something about our organization here today: We represent 90% of over-the-counter industry, including eighty manufacturers, many of which are here today. We are committed to promoting the role of OTCs and dietary supplements as well in America’s healthcare system through science, education, and advocacy. We provide leadership, guidance on regulatory and scientific affairs to Congress, state legislators, federal, state, and international government agencies. And we do a lot of educational work in providing tools and information with partners across the globe – basically to ensure the safe and responsible use of OTC medicines.


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Today’s presentation will touch briefly on five areas: ● the role and value of OTC medicines ● the quality metrics definitions that we have discussed in some of our trade association committees ● the data reported and calculation issues that we have ● the implementation suggestions that we have for you, and ● a couple of thoughts on the optional metrics for OTC medicines that you asked for.

Role and Value of OTC MedicinesThirty years ago FDA commissioner Charles Edwards stated that the Food and Drug Administration accepts the concept of self-medication. The consumers demanded it, the law provides for it, and in fact, it is a vital part of our nation’s healthcare system.

There are a number of medicines subject to NDAs, but the majority of OTCs are covered through FDA’s OTC review monograph system. Those monographs cover 300 ingredients, and hundreds of thousands of products, ranging from skin protectants (fairly low-risk products) to diaper rash creams (a little bit higher on the risk scale) to analgesics and cough/cold products – none of which are subject to shortages, if you have been browsing through Target or CVS recently…. 60% of the medicines sold in the US are OTCs.

The role and value of OTC’s: The strengths are rooted in the access, affordability and…trust.

I will speak to affordability. We looked at OTC medicines in seven treatment categories…and we found OTC products save the US healthcare system saves $6-$7 for every dollar that is actually spent by consumers. So, without access to OTCs, consumers resort to more expensive treatments like doctors’ offices, emergency rooms, and prescription medications for minor ailments that drive up costs.So let me get to the comments about the quality metrics.

ReportingWe can highly support the agency’s intention to use quality metrics to develop efficient and effective risk-based inspection systems to monitor the drug industry.

But this is a brand new area for FDA and some of the industry. The combination of the number of sites and products represents a ton of data to receive and process. We strongly support a concept of limiting this program to a small set of data points to begin with, and one that is limited to high-risk products and facilities.Supply chains can be really complex, including multiple sites and partners internal and external to the facilities. So reporting by site… will help avoid burden and focus on site level assessments.

There are a few specific considerations for OTC producers. Many of our companies are part of ISPE and the pilot, and we support many of the issues that Diane just mentioned.

But we need clarity, or flexibility anyway, in regards to how products are grouped for reporting, since there is no application numbers for OTC monograph products.

And secondly, the proposed text field commentary is important to provide context and insight, and provides opportunity to better interpret the data. For example consumers often comment on OTC products. The field can be used to clarify potential complaints versus just a comment.

DefinitionsWe have had a number of discussions about definitions. There are a couple that we will point out and comment on:

● “Specification-related” is often difficult to interpret.

● What is meant by a “product complaint?” Is that the comments? Unrealistic expectation for an acne product. Isit an allergy to one of the ingredients, even though the allergy warning is reproduced three times on the package? We need some definition….




● Even an apparently simple number like ‘the number of products produced at an establishment’ can bemisunderstood for OTCs. Is a hand crème and a topical analgesic produced in the same facility two products or one product? How are the SKU’s treated? Is a 24 or 48 pack of the same product counted as one or two?

We are certainly committed to working with FDA to improve the reported data and definitions…. Until we get an agreement on definitions calculations of metrics becomes difficult.

CalculationsLot acceptance rate can be useful, but without proper…rejected lot definitions, it is of little value.The product complaint rate: Is that limited to a serious adverse event reports? And this metric also depends on the size and seasonality. RX vs. OTC, private label vs. branded. And a better number might be per one million units shipped.

Most of our members think that the invalidated 00S is based on the quarterly defined metric. We hear that over and over again, and we need to work on that or else that calculation will be of limited value.

The annual product report within 30 days is difficult for some of manufactures that we have – they have suppliers all over the world – and using 60 days may not be a useful number.

Beyond that, consider having each site report their specific product metrics, rather than having one establishment try to consolidate all the product metrics from the various sites.

ImplementationImplementation of quality metrics reporting should begin with high-risk products in facilities, with reporting timelines established after the guidance is finalized. We recommend at least one public meeting for the agencyto describe in detail how this information will be used.

We think you will find that trends within the sites over time may be a more appropriate number than the actual number. And the frequency of revisions to the required data can be a concern.

So there is a strong possibility that other objectives will be useful as you evolve this program. But how does the agency intend to communicate this to the industry? Do we have to comment on guidance every time a metric or data expectation has changed?

Optional Quality MetricsA couple of comments on the quality of optional quality metrics:

So senior management engagement: As evidence of manufacturing robustness and a commitment to quality, a review and approval by the head of quality might not be the best metric. Active sharing with the management is better than the potential rubber stamp. [Is this] best addressed during inspections rather than reporting.

The leading indicators, process capability indices. If the company reacts to the…signals, we support collecting these leading indicators, with some indication of the manufacturer’s reactions to the index.So we think, for now, the fewer metrics calculated the better.

RecommendationsWe just have a few recommendations: Some definitions are still not clear – specification-related product complaints especially and the invalidated OS.

Again, begin with high-risk products in facilities. We do not believe that you should add excipients, APIs, and certainly the medical gases at this time.

Reporting could be timed to the annual product review cycle since every report is another burden for both the industry


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and the agency. But more importantly, having each site report their product specific metrics, rather than having one establishment try to consolidate the product metrics from one site, is far more important.

Consumer contacts are often higher for OTC’s and clarification on complaints is still needed. The text field can be very useful for this if you expand it, and use it as a search field, and review it.

So this is a challenging new program. We think you should start small, learn, and revise. And that is all the comments that I had.

PDA (JOHNSON)

Thank you for the opportunity to be here. It is my honor to represent PDA here. But, I would also start by saying many of the members of the PDA metrics task force are here in the audience. So, depending on how the questions come forward I may call upon some of them to help me.

A little bit about PDA. We are a not-for-profit individual member organization. We have been around almost 70 years. And, specifically, we have been very involved in this topic about quality metrics over the past three years, and we will continue to do so.

We really appreciate FDA’s involvement with us on quality metrics over those three years, and we look forward to continuing dialogue and partnership. We think that FDA has done a very good job working with industry to develop this document [that can be valuable] for the industry and for the patients that we serve.

PDA agrees that the proposed regulatory relief in inspections and post-approval changes are key to helping drive this program and increasing quality and benefits for patients. So the goal of this is to use the metrics to try to drive those kinds of improvements.

We do believe that continuous improvement for processes and quality systems is fundamental and can only be achieved when firms measure what they hope to improve. This guidance is a positive step towards changing the way that we address quality in our firms – not just focusing on compliance, but focusing on true quality. One of the outcomes of this will be to help us prevent drug shortages.

Having said all of this, we do believe that quality metrics is a journey. This journey has started and will continue. In order to achieve the best value and drive the right behaviours, there is going to need to be continued dialogue and modification as the program ensures.

We have heard some of the previous speakers speak about quality culture. PDA definitely feels that quality culture is very critical. However, quality culture is not an easily measured metric, and it may be better assessed through their onsite assessments of some of these key quality culture attributes. Having said that, PDA continues to develop tools to assess and improve quality culture, and we welcome the involvement of other stakeholders such as the FDA in that activity.

From the beginning, PDA has believed that trending of metrics within a site or within companies or within products is a better assessment than a direct comparison of individual data points. That is even true within similar products or similar manufacturing sites.

Those were my general comments. For the specific questions presented, I do have some responses to a few of those. We will submit written comments to all of them to the docket.

PHRMA (JACKSON)

Good morning. My name is Camille Jackson, and I am speaking today on behalf of the Pharmaceutical Research and




Manufacturers of America, PhRMA. PhRMA appreciates the opportunity to participate in this public meeting and share its views on the draft guidance for industry entitled Request for Quality Metrics and the agency’s plans associated with the quality metrics program.

PhRMA is a trade association representing the leading biopharmaceutical companies devoted to discovering and developing innovative medicine that enable patients to live longer, healthier, and more productive lives. Discovery, development, and delivery of safe, effective, and quality innovative medicines to patients is the core mission of our members, and achieving this goal depends on an FDA that advances public health by providing timely, science-based, and, in many cases, risk-based regulatory decisions. The FDA’s mission is to protect and promote public health by assuring the safety, efficacy and quality of human drugs and biologics.

Biopharmaceutical companies share the agency’s commitment to serving public health. We do this by researching, developing, manufacturing, and delivering innovative, safe and effective medicines to treat devastating illnesses such as cancer, diabetes, and Alzheimer’s disease.

A major part of our efforts are to develop, implement, and maintain robust quality management systems to assure the quality of innovative medicines. Just as FDA does, we believe quality is the underpinning of safety, efficacy and the reliable supply of medicines.

PhRMA applauds FDA’s intent to develop programs to mitigate drug shortages, to implement risk-based inspections, and incentivize modernization of manufacturing and quality systems, including FDA’s efforts related to the quality metrics initiative.

Our members are conducting a thorough review of the draft guidance, and PhRMA will submit written comments to FDA for considerations at a later date in response to the draft guidance and the specific questions raised in the associated Federal Register notice.

Four Key PointsOur comments today, however, will focus on PhRMA’s initial feedback on the draft guidance under the following four key points:

(1) PhRMA supports FDA’s efforts to introduce a risk-based inspection program based on key surveillance indicators, and the use of improved risk-based principles to determine appropriate reporting categories for post-approval change management.

Since publication of the pharmaceutical CGMPs for the 21st century in 2002, FDA has promoted a vision of a maximally efficient, agile, flexible manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight. PhRMA supports this vision and acknowledges FDA’s efforts to implement it through the development of programs and guidances.

PhRMA has actively participated in these FDA programs, and our member companies have embraced these approaches in their operations. With the release of the quality metrics draft guidance PhRMA observed FDA’s intention to further incentivize quality, and promote quality culture throughout the sector. However, challenges remain in finding meaningful correlations between quality risk and discrete metrics that attempt to broadly measure performance, capability, and culture.

PhRMA also observes the need to balance the burden of reporting data by products and by manufacturing site against the potential value for both FDA and industry.

PhRMA also recognizes the need to take measures to avoid unintended consequences that could inadvertently punish strong quality performers.

PhRMA encourages the FDA to:


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● explain in more detail how the quality metrics information gathered by FDA will be used by the agency in furtherenceof its regulatory oversight activities

● provide a more detailed roadmap on the implementation of the quality metrics program as it relates to the FDA vision and its other existing and planned regulatory oversight activities, and

● continue the ongoing global effort to harmonize aspects of post-approval change management, in particular,through the development of the new ICH Q12 guideline entitled ‘Practical and Regulatory Considerations on Pharmaceutical Product Lifecycle Management.’

(�) PhRMA encourages FDA to pursue a science-based approach to the quality metrics program.

The manufacture and supply of pharmaceuticals is complex and involves diverse product types, global supply chains, and technically complex manufacturing processes and procedures.

As manufacturers of innovative medicine, our members recognize these challenges and internally establish appropriate management oversight programs, including company-specific metrics to assess risks, define internal audit programs, and determine improvement priorities, resource allocations, and investments.

Thus, PhRMA members are well positioned to observe that the FDA approach to the quality metrics program is ambitious.

While PhRMA acknowledges FDA has incorporated many aspects of the technical and operability discussions with industry stakeholders to date, it is most important that the program is scientifically robust and that the collection and analysis of quality metrics data does not overwhelm industry and FDA.

Based on a preliminary analysis of the draft guidance, PhRMA has identified challenges in the scientific robustness of certain proposed metrics and the burden of reporting these data.

Therefore, to derive the optimal benefit from the program with the most effective use of FDA and industry resources, PhRMA encourages FDA to:

● continued productive dialogue with stakeholders, including PhRMA and our member companies, on the technical and operability aspects of the program, as more specific details are announced and implemented by FDA

● develop mechanisms for technical support and stakeholder engagement to ensure consistency ofinterpretation of the definitions of the data and metrics requested

● engage with technical experts in data analytics to establish correlations between recorded metrics and the associated analyses of the effectiveness of the quality metrics program approach, and

● establish data reporting and analysis mechanisms that minimize the resource burdens to both industry and FDA.

(�) PhRMA encourages integration of all FDA surveillance activities and indicators through strong collaboration between CDER, CBER, CDRH, and ORA.

With respect to regulatory oversight by FDA, operational and program alignment across FDA offices and centers is critical to achieving the 21st century vision for pharmaceutical manufacturing, including the specific objectives of the quality metrics program.

PhRMA welcomes FDA’s alignment efforts to date, including: ● the collaboration of CDER and CBER in co-issuance of




the draft quality metrics guidance ● the published FDA Program Alignment Action Plan for Pharmaceuticals between ORA, CDER, and CVM ● the establishment of the Office of Pharmaceutical Quality (OPQ) within CDER, and ● the New Inspection Protocol Project involving CDER, ORA, and the other FDA functions.

PhRMA encourages FDA to pursue:

● continue strong collaboration between CDER, CBER, CBRH, and ORA in the design and delivery of the quality metrics program and further alignment of FDA surveillance programmatic efforts

● continued progress on other risk-based approaches to inspections, with additional opportunity for input from stakeholders and technical experts, and

● consultation with other international regulatory agencies and the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme (PIC/S), as appropriate.

(�) PhRMA encourages the implementation of the quality metrics program in a stepwise fashion through rule making.

As stated, PhRMA observes that the quality metrics program as outlined is ambitious. The understanding of the science and data analytics needed to derive benefit is evolving, and there are challenges to implementation, including reporting burden.

In order to achieve the objectives of the program, PhRMA recognizes the need to overcome these challenges in a stepwise fashion through consensus with stakeholders to ensure the program operates as intended.

Additionally, because this program is being implemented through draft guidance and not notice-and-comment rulemaking, PhRMA is concerned that FDA lacks the legal authority to require manufacturers to develop and submit the requested quality metrics data, which is not currently a requirement in the CGMP regulations.Accordingly, if FDA seeks the mandatory program, the agency will promulgate new requirements through binding rulemaking.

In addition further details on the utilization and availability of metrics to manufacturers and other parties, including the public, is needed to avoid unintended consequences if the data were taken out of context, misinterpreted, or misused.

For these reasons PhRMA strongly recommends that FDA should:

● begin with a small number of metrics

● introduce the program in a stepwise fashion

● update the cGMP regulations through rulemaking if it seeks to create a legally binding obligation for amandatory data collection program, and

● clarify the agency’s plan for disclosure of quality metrics data.

Concluding RemarksPhRMA would like to thank the FDA for the opportunity to participate in this public meeting. As stated our members are conducting a thorough review of the draft guidance, and we will provide written comments at a later date in response to the draft guidance and specific questions raised in the Federal Register notice.

Both FDA and biopharmaceutical companies have significant responsibilities to safeguard and improve public health.


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In summary:

● PhRMA supports FDA’s intent for a quality metrics program as a means of advancing public health, and

● PhRMA and its member companies remain committed to working closely with FDA and all of its stakeholdersto establish a science-based, risk-based approach to developing and implementing a quality metrics program.

GPHA (GAUGH)

Thank you Brian and thank you panel for this opportunity to speak about a very important topic – quality metrics. I am going to be presenting on behalf of the Generic Pharmaceutical Association. My name is David Gaugh. I am the senior Vice President for Science and Regulatory Affairs at GPhA.

GPhA members manufacture more than 90% of all generic pharmaceuticals dispensed in the United States, and the products are used in more than three billion prescriptions every year. Generics represent greater than 86% of all prescriptions dispensed in the United States….

In 2013 GPhA pulled together from many of its strong member companies a group of about fifteen of the global quality technical experts within the generic pharmaceutical industry. Those fifteen representatives that sit on our Quality Technical Grouppanel represent about 77% of the supply of that 90% that I mentioned a minute ago….We have over 70 companies that are engaged as members of GPhA that are assisting us as we go forward in any of our work and working groups and opinions that we present here today and at other meetings as well.

From a quality technical group perspective, our vision statement is: The Quality Technical Group meets patient needs by assuring accessibility to affordable, quality medicines; ever mindful of the essential role the generic industry plays in healthcare and the healthcare system.

Our mission: ● We are a unified in voice for quality in the generic drug industry. ● We champion and influence continuous improvements of industry quality standards, actively leading their development, education, and communication. ● We work in partnership with global regulators and industry counterparts on quality initiatives that benefit patients ● And we are committed to providing dependable, sustainable value in healthcare systems across the United States.

Patient safety and product quality: GPhA members produce high-quality medicine, and we look forward to working closely with the FDA to develop drug quality initiatives that will facilitate this goal.

GPhA championed GDUFA over three years ago in order to provide enhanced risk-based FDA inspection oversight of the pharmaceutical industry around the world.

GPhA members strive to work closely with the agency on quality initiatives that detect emerging manufacturing issues, which would allow for early discussions between FDA and manufacturers to proactively resolve any potential issues.

GPhA members commend FDA for continuing to work on ensuring that inspectional approaches focus on our shared goal of providing high-quality drugs to all patients.

GPhA members believe that the agency will need to look beyond regulatory compliance in order to successfully evaluate drug quality.

It is part of our shared responsibilities to ensure that America’s healthcare system stays at the forefront of quality and innovation. Supporting the FDA’s ability to perform its critical review and subsequent monitoring of new medicines in a timely and effective manner is one way that our industry can continue to serve patients.




FDA’s draft metrics guidance is based on good intentions but may exceed FDA’s statutory authority.

FDA’s mandatory inspection authority beyond the U.S is not clear. Therefore, the authority to demand metrics would not extend outside the United States.

Requesting metrics in advance of inspections: Inspections are records companies already keep…and there is no authority to require manufacturers to generate new records for investigations.Metrics are not necessarily kept in a way that FDA has prescribed. FDA has commented that there is no standard approach to keeping metrics in the industry. Information about contractors and suppliers may not be available as specified in the draft guidance.

Failure to supply metrics consequences: It is deemed by the FDA as equivalent to refusing an inspection and may render products adulterated. Refusing metrics is not necessarily refusing an inspection.

Guidance imposes binding rigid rules: It provides no practical alternative to comply due to its prescriptive nature. It tracks performance versus 30-day deadlines on APR’s and for batch disposition that are not supported by the rules.

It imposes de facto increased inspection penalties for failure to report voluntary information. There should be no penalties for not supplying this voluntary information.

And metrics requested are not reasonable as guidance defines. FDASIA requires that requests be provided within a reasonable timeframe, within reasonable limits, and in a reasonable manner, but what the guidance specifies is not reasonable in our opinion.

Risk-Based Inspection SystemsFDA’s risk-based model should hold all suppliers of all drugs to the US to the same quality standards regardless of whether they are located in the United States or abroad.

Prioritize FDA’s focus to those suppliers that FDA has never inspected, not inspected within the last four years, and those with a history of serious compliance problems. And strictly monitor those suppliers in industry who have not demonstrated a commitment to quality and/or a lack of record of ensuring quality.

FDA’s risk model should not over inspect large manufacturing sites just by virtue of their size, and affect the cost of generic drugs by virtue of undo metrics burden.

BurdenThe burden needs to be reasonable and realistic. Paperwork Reduction Act estimates are grossly underestimated and need to be included in all actual metric processes required to assure realistic characterization of the burden. FDA should provide the means to report metrics on a site basis instead of a product aggregation.

Contractor reporting is heavily burdensome. FDA should request metrics directly from the contractors in keeping with their direct regulatory relationship with them. FDA should not request application holders to gather and compile data for contractors given that contract holders are not parties to the contractor of the FDA inspections.

Internal use verses reportable to an agency: Internal metrics collection processes and systems will need to be bolstered to provide 100% traceability as external reporting to the agency. Infrastructure and systems to support metrics reporting externally will require significant, added out-going costs that must be factored into this burden.

And time to prepare: At a minimum, provide the safe harbour period FDA had communicated prior to the draft guidance in order for companies to prepare for accurate, meaningful metrics reporting. An incremental approach is recommended as well as the use of pilot(s) to determine the effectiveness, and allow FDA better understanding of

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how to utilize this data.

Although FDA has engaged with industry, there are many surprises in the guidance that have not been fully vetted and that create a significant burden and complexity for the industry. An example would be product level reporting, and the idea of covered/reporting establishments. And the process now seems unduly rushed, considering the significance of this initiative.

Unintended ConsequencesThe potential for drug shortages: The companies that make low-volume products in one campaign per year may require a different look at metrics than some of the other manufacturing models. Companies may be incentivized by FDA metrics to make choices on products and sites to the detriment of the drug supply – for example, discontinuing difficult-to-make products or US production at certain sites.

Potential for gaming the metrics: Putting products on hold rather than rejecting them among others, and avoiding retraining of personnel as a practice. The agency should develop a process that could monitor these issues carefully.

Potential for increased inspections: Production volumes, launches, and narrow therapeutic range products may flag manufacturing as inherent risk regardless of good quality metrics performance. FDA should make metric definitions clear using industry feedback and provide ability to have the metrics context included and prevent misinterpretation.

SummaryI think you have heard from several groups today that would get into the process of maybe slowing down just a little bit. I will even steal from Diane [her] four simple words: ‘start small, learn, and evolve.’ And I think you have heard that from all of the presentations that have been up here. Because what we do not want to do is get into unintended consequences once we launch this project and get underway.

As I began with this, GPhA is very interested in working with the agency and helping the agency get to the goal that we all wish to get to, which is to improve product quality and mitigate drug shortages.

As FDA moves forward with its quality initiatives, we look forward to an ongoing dialogue with the agency.I would have one other request: Because it is less than 30 days out from the time that the guidance actually came out to the holding of this meeting – and we are learning a lot from this meeting, from both the presenters on the panel and the presenters from the audience – we have already put in a request for an extension on these comments and we would ask that that request for extension be considered.

IPEC-AMERICAS (ZAWISLAK)

Good morning Brian. Thank you and thanks to the panel. My name is Priscilla Zawislak, and I am here representing the International Pharmaceutical Excipients Council (IPEC) of the Americas today. IPEC-Americas is a nonprofit trade association comprised of excipient manufactures, distributers, and users from the pharmaceutical industry.

Thank you for the opportunity to speak regarding the draft FDA guidance regarding quality metrics. I am here today to speak specifically to question number four regarding the correction of metrics from high-risk excipients.

There is currently no definition for high-risk excipients, and it is the position of IPEC Americas members that, for the risks that might be considered for this guidance, it is not the manufacture of the excipient, but rather their use in high-risk products and/or applications.

Quality metrics, including those proposed in the FDA guidance, are based on the manufacturing process. Most of the issues associated with excipients being labeled as ‘high risk’ have been related to issues that have occurred in the supply chain integrity or economically motivated adulteration and are typically not related to the manufacturing process.




Often the same excipients are used in a variety of applications. Some may be considered ‘high risk’ and others may be considered ‘low risk.’ This makes it nearly impossible to assess whether the excipient should be considered high risk or not relative to quality metrics for the manufacturing process.

On a second topic also related to the topic of excipients, some excipients are used as ‘atypical’ actives in both over-the-counter and prescription drugs, often without the excipient manufacturer’s knowledge. Since this proposed

guidance will include API’s, IPEC-Americas would like to understand how this would impact excipients that may be used as ‘atypical’ actives.

Since the guidance is so new and there are so many unanswered questions for even the finished drug product, it is IPEC-America’s position that the guidance should be finalized and unanswered questions be resolved for drug products/drug substances before considering whether to apply quality metrics for any excipients.IPEC-Americas will be submitting written comments to the docket before September 28th, and thank you for the opportunity to provide these comments today.

PBTF (NICHOLS)

My name is Alan Nicholls, and I am speaking on behalf of the Bulk Pharmaceutical Task Force this morning. For those not familiar with the Bulk Pharmaceutical Task Force, we are an affiliate of SOCMA, and we are an association of manufacturers for active pharmaceutical ingredients, excipients, and pharmaceutical intermediates.

Our overall comments on the guidance for industry are as follows:

● We opine that the agency needs to provide greater clarity for reporting directives and definitions in the guidance.

● We recommend that the FDA follow ISPE recommendations to initially avoid inclusion of quality culture andprocess capability metrics.

● In regard to the alternative approaches proposed by the FDA, BPTF supports allowing a manufacturer to useits current timeframe for conducting for its annual product review, or in our case a product quality review, as a timeframe for reporting quality metric data. We think this will be very helpful to API manufactures to use that timeframe. Also we think it is probably useful to the agency in not getting all the data at the same time. So it is like a win-win there.

● And finally, we certainly support the inclusion of a tech field for explanation of unusual data or trends. We can’t see any downside to this – we only see upsides.

We do wish to point out that we had some questions on a couple of areas of the guidance. In the short time that it is available today I just want to cover a couple of these.

The first one is the section that says who reports for covered establishments. Our question is, who is required or allowed to report the quality for APIs? It is not clear in the guidance.

Also in the glossary area, we have questions about two definitions: The first one is ‘lot attempted,’ and the second is ‘lot release test.’

Reporting Directives for APIsWith regard to reporting directives for APIs, the guidance states: ‘ FDA intends to ask industry to submit one report for each finished dosage form product and one report for each API of a covered drug product.’ It also states that: ‘FDA believes that…one establishment will already possess or have access to all of the quality metrics data needed to submit such reports’.

This left us with the impression that finished dosage form manufacturers will be expected to report the API quality data. But there are certainly several situations where this could be very problematic.


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What about API purchased by multiple customers? If we submitted the data to all the customers the agency would see the data from each of the customers and they would get multiple submissions of the same data.The alternative is for the API manufacturer to supply only the data for each customer. This would prevent, of course, double counting, but it also not the way that we store data. So therefore, it would put a lot more burden on the API manufacturer.

Also then, what about where we have one lot manufactured by multiple customers? You could be manufacturer of a lot and have five small customers purchase several drums from that lot. Who gets the data?I think we split down the middle in our membership initially when they read the guidance as to did the agency intend for direct submission by the API manufacturer or did it have to be by the finished dosage form manufacturer.

Relief comes in looking at the webinar in that there is a statement in the webinar that states that when we look at the webinar and there was a statement in the webinar that a holder of the API DMF may submit a report directly to the FDA and list each product that uses the API.

However, that does not appear in the guidance, and it did not even appear on the slides associated with the webinar. It was just a statement that was made. We certainly hope that the agency is offering this option that we strongly support. But that sort of information definitely needs to be in the guidance.

Another question that came to our mind in this area was: Should the data include lots from API that are exported and not used for a covered drug product? For example, if you make 20 lots a year, 15 of them go domestic, five go to Europe to make drugs over there that are not sold back in the US and therefore are not covered drug products, does the agency want us to include the data for the whole 20 lots or data for only 15 lots? Again, one would have to sort the data out and that could be more time consuming. So we need some more clarity there.

[On] how to do this, we would say that the agency needs to put more examples into the guidance than exist now.

Definitions of ‘Lot Attempted’ and ‘Lot Release Test’The definition for the lot attempted – I won’t read it out but that is the definition that appears in the guidance: [‘Lot Attempted – a lot intended for commercial use for which the manufacturer has issued a lot number and charged API (for finished drug manufacturers) or primary starting materials (for API manufacturers).’]

If you see or hear the webinar, there are certainly more examples provided there. These examples should be included the guidance, because not everybody is going to go to the webinar and it is not going to get as wide coverage, and the guidance is the official document.

In addition, we think there actually should be further examples and clarification in the guidance, such as answering the question, if a lot is reprocessed or reworked, should it be counted as one lot, or counted as two lots? Do you want to count it first as a failure and then as a pass, or do we only count it once as a failure?

The lot release test: Again, the definition is as written there: [Lot Release Test – includes all finished product tests, all real time release tests, and all in-process tests that act as a surrogate for finished product lot release.’]. I just want to point out that it is common practice to run analyses in duplicate – these are often called two weighings or two sample preps – and then you report the average result as a release value.

It is also standard practice to make more than one injection for chromatographic test. So what should be counted as a lot release test? The recorded release value, results from each of the weighings, or each of the injections? So you have the possibility of a 1, 2, or 4 scenario there. As far as we could see there was no guidance in the guidance regarding that subject.

We do intend to provide more detailed comments on the guidance as well as responses to some of the questions posed in the Federal Register, and these will be submitted by the Bulk Pharmaceutical Task Force in the comments to the docket.

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Stress studies are playing a key role for Roche/Genentech in the comparability assessments needed to support its transfer of biomanufacturing processes between sites, reflecting the time savings, sensitivity to differences, and a high level of stability assurance that they provide.

At the 2015 Latin America CMC Strategy Forum held in Brazil’s capitol city Brazilia in late August,.Roche/Genentech Global Biologics Manufacturing Science and Technologies (MSAT) Group Lead Mary Cromwell highlighted the role that the stress studies are playing in her company’s tech transfers.

Cromwell’s remarks have high relevance to the dialogue around lifecycle management and evolving and harmonizing the post-approval change regulatory paradigm to better accommodate the realities of global manufacturing and supply operations. Roche’s approach to evaluating biotech manufacturing site transfers suggests a potential model for what a global comparability protocol might look like if the ICH Q12 effort were to take that direction.

Cromwell began her presentation on “How to Overcome the Challenges of Stability Studies to Support Global Tech Transfers” with a review of the different forces that are driving Roche to do manufacturing relocations on a not infrequent basis.

Among the drivers are the need to: ● increase capacity –either due to increased demand for a product or theneed to clear in-house space for new products, which need more nurturing ● have dual sourcing to de-risk supply – with both fires and earthquakes, for example, in play inCalifornia ● insure against equipment failures, which can shut down production lines, and ● enable and respond to facility closures – for example, due to compliance concerns and/or changes in a CMO relationship.

The company’s tech transfer goals are “pretty simple,” Cromwell explained: ● to transfer the same process, making only modifications needed for facility fitting purposes, and ● to maintain comparable product quality/stability.

The assessment process focuses on demonstrating the comparability of the yields at the two sites, of product quality, and of the analytical methods.

Roche focuses, in particular, on the stability considerations, which can “often get left behind” in concentrating on release testing and extent of characterization, such as potency assays. Stress studies, in turn, form the foundation for the stability assurance.

Stress Studies Provide Leverage for Faster Regulatory Clearance

Cromwell, whose MSAT group has oversight responsibility, notes that Roche/Genentech has “somewhere between 30 and 40 active tech transfers going on in our biologics network. So we are dealing on a daily basis with what is required for our technology transfers.”

The requirements for the new manufacturing site vary significantly by region and “are evolving on an almost daily basis,” she said.

The US and Europe recognize the role that stress studies combined with product knowledge can play in assuring comparability, resulting in a faster clearance process. By contrast, elsewhere in the world Roche is seeing the requirement for a full stability package for changes, with the potential for staggered clearances to add significant complexity to managing the manufacturing network and supply chain.

Cromwell then delved into how her company is using stress studies “to give us the confidence that the material we are producing at the two sites is not different – or in some cases, is different,” and the studies “tell us what we need to do next.”

Roche uses storage conditions for the study that are typically at a higher temperature than the accelerated conditions based on product knowledge, which can give “meaningful information” fairly rapidly, depending on the product.

Side-by-side comparisons are generally done on three lots from each of the sites. The assessment includes a qualitative and quantitative comparison of all the stability indicating attributes and a statistical comparison where meaningful.

The stress studies give Roche “a fairly quick understanding” if there are potential differences, either in the degradation rate or mode. They are “much more sensitive than compared to real-time storage,” which for some attributes may not show change over the product shelf-life, and “really giving

Stress Studies Are Playing Key Role For Roche/Genentech in Assessing Biomanufacturing Process Site Transfers

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us a high assurance of comparability at the recommended storage temperature.”

Three different aspects are explored through the stress studies: ● overall behavior, a qualitative assessment of sameness ● mode of degradation, typically done with chromatographic and electrophoretic methods, and ● rate of degradation typically on two or three attributes, employing a statistical evaluation of the stress data.

The rate of degradation, in turn, is assessed in two-stages: ● homogeneity of slopes to determine if there is any evidence that the rates are different, and ● ratio of rates, which explores if the rates are the same. “Which question you can actually answer,” Cromwell explained, “depends on the quality of your data and how much change you are seeing.”

After reviewing the details of Roche’s stress study approach, Cromwell provided three actual case studies involving liquid and lyophilized products illustrating what the evaluation looks like in practice and the response that follow when results differ in the comparisons.

With their sensitivity to minor differences, “stress studies do provide valuable information to support comparability,” she summarized, and understanding those minor differences “still gives us a path forward to show comparability in a much faster way than if we rely on real-time stability.”

With a stress study, she emphasized, “we can reduce the time depending on the product from two to six weeks to get this assessment done. It gives us a high degree of assurance that the material produced at the two sites is comparable and will meet its shelf life expectation.”

Influenza Vaccine Shift to Brazil Also Explored at Forum Session

The presentation by Cromwell (included in full below) was one of three at a session of the Brasilia forum exploring the issues around technology transfer for biopharmaceuticals. Also presenting were Claudio Cabral from Brazil’s Instituto Butantan and Biologics Consulting Group (BCG) expert Chrisina Vessely.

Cabral focused on the practical experience and lessons learned during the challenging and lengthy tech transfer of influenza vaccine production from Sanofi Pasteur to the Brazilian institute.

Motivating the transfer was the need for Brazil, like other developing countries, to have the ability to meet the vaccine demands created by influenza pandemics. Cabral stressed the “solid partnership” that was required to transfer a complete complex production process and make possible

the joint development of new competencies, improvements to the product, and further innovations.

BCS’ Vessely focused on the analytical methods handoff -- how it is pivotal to the overall success of the biomanufacturing transfer process, the different problems that can occur if that methods handoff is not done mindfully, and how firms can deal with the challenges involved (see pp. 47-54).

Vessely echoed Cromwell in stressing that the key to a successful transfer is demonstrating the analytical comparability of the drug substance produced at each site, pointing out that the need for clinical studies may hang in the balance.

Following the foreign CMC Strategy Forum pattern, the two-day Brasilia meeting included updates on the recent biotherapeutic regulatory trends in Latin America related to “convergence, predictability, transparency and priority reviews” from various of its agencies including those of Brazil, Peru, Chile, and Mexico, as well as updates on these issues from European and the US regulators.

Along with tech transfer, other technical sessions at the forum addressed: ● cold chain management and qualification for biologic product transportation, and ● the characterization, control and regulation of protein glycosylation.

Drug Substance Comparability is Key

During the panel discussion at the session on biotech site transfers, the panelists delved further into stress studies, what should be considered and reported, ways to reduce costs of the studies, and the role of new technologies.

Cromwell explained that while her examples of stress studies for APIs involved high temperatures, there are other ways to stress a protein. The key, she maintained, is that if the material breaks down the same way for both the drug substances being tested, that is “pretty strong evidence that it is going to behave the same in the drug product.”

If that is the case, she said, her company would put forth a scientific justification of why it would not necessarily include the drug product information in the drug substance transfer. Instead, the material would be put on stability and reported at a later time rather than in the same package.

FDA Office of Biologic Products (OBP) reviewer Sarah Kennet agreed with that approach, noting that the agency “most of the time” would not expect the drug product stability data to be in the transfer package. However, the




agency would expect the drug product lot to be placed on stability and reported in the annual report.

In response to a question regarding the cost of tech transfers, Cromwell explained that “significant” costs can be incurred due to the amount of API that is required for validation studies. She also explained that the cost is not only the value of the API, but the time used to produce it, and the opportunity cost of not using that time to manufacture other products.

“Whenever possible,” she said, Roche will use a surrogate for the API as part of the drug product process validation. “Some authorities are more comfortable with that than others,” she commented.

Another way to reduce costs for lyophilized products – a product type where Cromwell sees the most potential for variability – is to use a risk-based approach to justify the use of fewer batches. For example, while a typical validation would include three batches at both the maximum and minimum lyophilization loads, she would propose two batches for one condition and one batch for the other, using a total of three batches rather than six, and then evaluate the data using a matrix approach.

Cutting Edge vs. Broadly Available Technologies

Regarding the analytical characterization of transferred products, a participant asked the panel to comment on the use of “cutting edge” technologies vs. their availability in emerging markets.

BCG’s Vessely commented that companies have a choice of which technologies to use during development, and need to balance the output of the method against the availability of the technology.

She cited an example of using HPLC vs. UPLC, noting that while UPLC may produce better results, it is more resource and capital-intensive and may not be readily available at CMOs or in markets where the product may end up in the future. She recommends taking a look up front at the options and whether the “slightly less advanced method is going to give you the same output. Is it going to be sufficient for characterizing your product?”

Cromwell explained that a frequently used approach at Roche/Genentech is to couple new technologies with new products.

“So it is incorporated as part of the licensure for that particular product and is introduced slowly into either our manufacturing or quality network so that we can get

experience in the commercial setting with that particular technology – whether it is manufacturing or analytical.” Once experience with the technology is gained, it can then be moved out to other products with the realization that there could be a regulatory impact and potentially multiple

filings required to support its use.

What Data to Submit?

The topic of what data to submit for a tech transfer and how much data is needed was also explored during the panel discussion.

Kennet commented that OBP’s “biggest problem” is with sponsors not submitting “enough data to support the transfer.”

In other cases, the OBP reviewer said, “we get sent data and do not have a complete enough picture of what the changes were, and it becomes harder for us to evaluate the data if we do not know what the changes were or whether the data they collected were really the right data that we want to see.”

She explained that “it helps us to have a really good description of the pre and post change. That might be a little bit more description than would be in a normal dossier.”

Regarding problems that can arise during tech transfers, Kennet commented that “we usually do not see the problems because they do not submit the problems to us. They do the transfer, they make it work, and then they submit what worked.”

BCG’s Vessely pointed out the importance of evaluating critical quality attributes and of having enough product history to appropriately set comparability criteria. “Make sure you have the right methods selected to do that analytical comparability and that you are not missing something that is critical.”

Cromwell commented that one of the topics of conversation her group continues to have during tech transfers is the selection of the appropriate acceptance criteria and how that is done.

She echoed Vessely’s comments that understanding product history and the criticality of the attributes are important, adding that her company often uses a statistical assessment. “So it is not just that the product meets specification, but that it meets a much tighter statistical control around several of the attributes.”

During the transfer, “a lot of attention” is paid to the process. The key is to ensure that the criteria is strict enough that after the transfer “when you do not have some many people


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so intensely focused on producing those three lots that you will still meet your overall acceptance criteria very easily.”

Vessely also provided a caution regarding the use of historical comparisons.

She noted that as the process is evolving over the course of the product lifespan, analytical methods are evolving as well. “Sometimes that historical comparison and that historical data set is not as meaningful as you would like it to be in setting your comparability parameters.”

As the methods evolve, it is important to understand the differences that can arise, Vessely pointed out. “Are you seeing different impurities? Are you seeing them at higher levels? So when you are comparing them to that historical process, if you see a sudden jump in levels of impurities you are reporting, you need to understand whether it is based on an improved method and not necessarily due to the process itself.’

Batch Selection, Bridging Studies Explored

The panel was asked to comment on batch selection and bridging back to previous versions of the manufacturing process.

Cromwell explained that Roche/Genentech does bridge back to all previous process versions when setting up acceptance criteria for a comparability protocol, taking into consideration whether doing so might allow a wider acceptance criteria.

“If we have a newer version and it would mean a tighter acceptance criteria, we may decide to choose that acceptance criteria.”

Regarding the stability portion of the exercise, Cromwell stressed that a side-by-side comparison is important.

“We have seen, for one of our products, when we attempted to compare back to historical data, a difference of two degrees in an incubator produced a rate that looked completely different. It took a while for us to figure out what was going on.” Without a well-controlled side-by-side study, she said, the data may “have led us down the path to see differences that maybe were not real.

”Regarding batch selection for the exercise, Genentech uses the first three consecutive batches that are produced. “As long as they are releasable, our approach is that those would be those batches. It is not looking at the batches and deciding

which we would use. It is predetermined.”

Test at Single or Multiple Sites?

The panel was asked to discuss the pros and cons of staging and testing stability samples at satellite sites as opposed to where the manufacturing and other QC testing is taking

place.

Vessely responded that she has seen issues when there are method differences between sites that have “not been reported up through the chain,” leading to the potential for seeing different impurities.

An additional issue when there is testing going on in different places is that “you have to manage that entire project differently.” On the other hand, she said, bringing testing from multiple sites to a single site “can be a bigger challenge than you might imagine.” She cited an experience at Merck when shipping material to a different site “took weeks to get the paper work through and get these to go. It was eye opening to me.”

Cromwell said, “I can echo that experience.” She pointed to issues that can arise – for example, regarding shipping validation.

“What is the controlled shipping around your stability samples and how certain are you that that is not going to impact the quality that is showing up?” She also pointed to the importance of having the right stability containers.

“There are a lot of little logistical details. I think at a high level everyone says, ‘stability, how difficult can it be?’ And then you find out that that is where the devil lives. I will say the first time we had the shipping validation issue, we had one site that would not release samples because they did not have the appropriate documentation, which no other site thought they needed. It is the little things that can impede your ability to do the studies.”

The Genentech official also noted that different computer systems at different sites that may not “talk to each other” can be problematic.

She pointed to the importance of getting data that can be used to accurately compare results from different sites. “It sounds trivial. But it is something that actually has to be coordinated very well. Otherwise you find that there are different significant digits being reported or different names for an analytical method. While it is all accurate for that one site, if you were trying to pull a comparison together, it just adds more to the complexity.”




GENENTECH’S MARY CROMWELL ON BIOMANUFACTURING TRANSFERS AND THE ROLE OF STRESS STUDIES

At the Latin America CMC Strategy Forum held in Brazil’s capitol city Brazilia in late August, Roche/Genen-tech Global Biologics Manufacturing Science and Technologies Group Lead Mary Cromwell explained the drivers for her company’s tech transfers, and how Roche uses stress studies as a key tool in assuring that the transfer has been successful.

I want to explain what my group does, because it is a long title that encompasses my group. I have the Global Biologics Manufacturing Science and Technologies group, reduced to MSAT when we talk about it. That part of my group is really responsible for two different aspects for our commercial products: One is a general product support in terms of the manufacturing process health. And the second part is being involved in the technology transfers when we specifically are going to contract manufacturing organizations. We spend a lot of time supporting tech transfers.

The other part of my group that I am not really going to talk about today is global packaging development. I think some of the topics that we are going to talk about in the sections later this afternoon in terms of shipping validation and how we do the tertiary packaging and things like that, my group also supports. We get involved in our commercial products

in many different ways.

Reasons for Tech Transfers

When we think about technology transfers, there are many different reasons that we may do this.

One of them, and probably our favorite one, is to increase our overall capacity. This can be due, in part, to overall global market demand for specific products. Especially when products are new and we are seeing increased clinical indications coming on into the marketed world, the demand for the product goes up. So to meet the capacity we need to increase our overall capacity in our network.

Also we have a strategy internally that if we have a new product, we want to manufacture that in-house in our internal manufacturing network. So to make room for that we would sometimes move our older products to contract manufacturing organizations.

The second reason, and this is a pretty big reason, is to have dual sourcing. Again, this could be just to de-risk the project because of demand variability. Some of our internal sites are in slightly unfortunate locations due to natural disasters.

For example, a couple of years ago in California our Oceanside facility came very close to wildfire. You don’t normally think about fires and what it does to your manufacturing network. But we became very acutely aware of the impact of fire in that particular case. Of course, being in California, we have earthquakes as well. So we do not want to have sole sourcing of those products. We want to be able to use another site.

Obviously, equipment failures: We had one example where we had one of our drug product pieces of equipment showing some issues and we ended up having to shut that line down for a month to fix that. Well, that means stopping production of all those products. We were able to shift our demand to other sites to make sure that we maintained supply.

The last reason is to enable facility closure, or in the case of a contract manufacturing organization, a facility exit. This could be because of older technologies and facility designs, where we are having trouble meeting current expectations for GMP. In the case of the CMOs, it may be that we have reached a crossroads in our relationship for many reasons, which also could be their compliance with health authorities.

For all of these reasons we do quite a few tech transfers of our manufacturing processes.

Just to give you a sense of the Roche Biologics Network, we have 11 internal sites, six drug substance and five drug


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product. And then we work with 37 contract manufacturing organizations. This is a pretty sizable number that we are looking at. I would say, of the contract manufacturing organizations, about two thirds of them are actually to give us capacity, and the other third is to give us access to technologies we do not have in house. So, for example, in the combination product device area we have CMOs that do the assembly of some of our devices. We have some CMOs that do filling of pre-filled syringes, which we also have the capability for in-house.

Tech Transfer Goals

We have some pretty simple goals with respect to tech transfers, usually:

One is, for the manufacturing process, we would like to transfer the same process. We prefer modifications that are only required for facility or equipment fit. Sometimes these modifications can be a little bit bigger than others. And as you will see when we get into the case studies at the back, sometimes we realize it was more complicated than maybe we anticipated.

Ultimately, the goal with the product is that we have comparable product quality, and that we can assign the same expiration dating for the material produced at each manufacturing site.

What I also want to point out with this slide is that whenever we are doing the comparability studies to support the expiration dating, we will do it at the site of the change. For example, if we are transferring a drug substance or API manufacturing process from one site to another, we will establish comparability of the drug substance and not establish it at the drug product level that uses those drug substances. Our basic premise is that if we can show comparability of the drug substance there is no need to further assess comparability of that.

Establishing Comparability

There a building blocks of comparability. The first is with respect to the process. You need to demonstrate, for example, that your yields are comparable from site one to site two.

Second is the product quality and analytical comparability. This is an area where there are different aspects that go into it. Typically when people think about analytical comparability, they tend to focus on the certificate of analysis or release testing and extent of characterization, which would be the analytical characterization and the bioanalytical characterization, such as potency assays.

What often gets left behind are the stability aspects of this as well. We look at this from two different perspectives: One is the use of real time stability, and with the challenges that presents with timelines, we use stress studies to support our real time stability really to help us provide a lot more confidence that we will ultimately meet our expiration dating.

To be complete, we also have clinical and non-clinical studies that may be required if we have substantial changes in the manufacturing process. For tech transfers this is rarely required – we rely mostly on the analytical and process comparability.

As Thomas [Schreitmueller] mentioned yesterday, the framework that we have to look at comparability is really coming from ICH Q�E. When we look at tech transfers, we consider this to be a relatively low risk compared to some of the other reasons you would be doing comparability. This is talking about changes in manufacturing process. Really for the tech transfers we are hoping that is minimized to only a change of site of manufacture.

In going through the different parts of the ICH Q5E guidance, I want to focus on the bottom two: One is the two uses of stress studies to establish the degradation pathways and to be able to provide a direct comparison of, in this case, pre-change, site one, to your new site, which would be post-change. The other is that you can detect potential differences that may be too subtle or actually invisible to detect by some of your other assays.




Health Authority Expectations

Right now with the Roche work plate, we have somewhere between 30 and 40 active tech transfers going on in our biologics network. So we are dealing on a daily basis with what is required for our technology transfers.

What we see varies by the region in which we are doing the licensure for the new manufacturing site. And the requirements are evolving on an almost daily basis.

Starting over here on the right where I have the EMA and FDA: In general, we get faster approval in those regions for tech transfers. Part of the reason for that is the reliance on the stress comparability studies. In the case of FDA, they expect us to analyze the results of those stress studies using statistics. And with those statistics is a high level of confidence that the product that you are producing is not different. In the EMA, we have seen that sometimes there is a requirement that is more of a nice to have than an expected to have. Then in both cases our product knowledge is feeding directly into some of the requirements for faster approval.

In the rest of the world we are seeing the requirement for a full stability package for changes. In this case I have included up to 24 months real-time. In some of our products we have even longer expiration dating, and so it could even be longer if we are required to support the full expiration dating. With that, we need a six-month accelerated stability at the time of the submission.

There are no statistics and there is no flexibility for acceleration. So in this case you can imagine if we are transferring our process from site one to site two, we could have very rapid approval [in the US and Europe]. Depending on the country, it could be very slow, and we essentially would be maintaining different support for the rest of the world because the licensure is lagging sufficiently behind.

If there is a manufacturing process change, which is really outside the scope of this presentation, you can imagine we are having to maintain different versions for different lengths of time, which then I will say when you manage a manufacturing network and supply chain, it becomes quite complex.

Stress Studies

Over the next part of the presentation I want to give you some understanding about how we use stress studies to give us the confidence that the material we are producing at the two sites is not different, or in some cases, is different, and tells us what we need to do next….

For comparability, we do stress studies selecting a storage condition that is typically at a higher temperature than the accelerated condition. For most of our liquid products it would usually be 40° C for a relatively short time, typically one month. But it does depend on the product.

Some of our products degrade very quickly, and we can get a lot of meaningful information in two weeks. Others degrade very slowly, even at high temperatures, and it may take three to six months. There is a lot level of product knowledge that goes specifically into picking this. We also include at least four time points so that we can do a statistical evaluation.

Our common practice is to do a side-by-side comparison of three lots – three lots from site one, and three lots from site two. This is to help us get some meaningful statistics about degradation rates. You can imagine if you have normal variability in an assay with one lot, you may pick up a difference that is not meaningful and is specifically around the one lot.

Finally, we do a qualitative and quantitative comparison of all the stability indicating attributes and a statistical comparison of some. Some attributes do not lend themselves to statistical comparison – for example, pH. That is something we want to look at. Did we make it the same? Did we hit the same pH limit? But when you start talking

One of the advantages of the stress studies, as I mentioned earlier, is that it is very sensitive. Because of the time


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frame when we can conduct these studies, we get a fairly quick understanding if we have potential differences, either in the degradation rate or in the mode of degradation. It is much more sensitive than compared to real-time storage, which for some attributes we may never even see a change over the shelf-life of a product. Again, just emphasizing, this is really giving us a high assurance of comparability at the recommended storage temperature.

So when we go into the three different aspects, the first one is the overall behavior. This really is a qualitative assessment looking at the stress test results for all of the attributes, things like pH and protein concentration as well as some of the more stability-indicating assays like size exclusion chromatography, where we look and say, ‘do these look the same?’

When you have scientists judging data they often can look at it and say ‘yes, this looks the same, or no, this looks a little funny.’ We want to have that assessment done side by side to say, ‘yes, this looks right.’ If there is a change, then it is monitored and compared over the course of the stress study. That monitoring and comparing may be just simply saying we see a 3% change with the new, 3% change in the old, and those look about the same.

The second one is the mode of degradation. This is where it is a qualitative profile comparison at each time point comparing the material from site one and site two. Typically this is done for the chromatographic and electrophoretic methods to look at the mode of degradation.

In this example, it is an ion exchange chromatography. There are a lot of peaks that show up here, which means that we have a lot of opportunities for things to look different, and, in this case, we are showing when you look at this, they look the same. There is no difference between site one and site two. And if I remove the labels, you would not be able to tell me which one is which. The things we look for are: Do we have new peaks? Are the overall peak shapes the same? And are they the same rank order with respect to peak height?

Once we have gone through that, we have come to the third part of the analysis. This is the rate of degradation. This is where we do a statistical evaluation of the stress data to look at the rate of degradation for usually only two or three attributes per product. There is a two-stage assessment of that rate:

● The first one is the homogeneity of slopes. This one is answering the question, ‘is there any evidence thatthe rates are different?’

● The second one, the ratio of rates, is asking the question, ‘are the rates the same?’

That seems like it should be the same question, but it is actually two different questions. It depends on the quality of your data and how much change you are seeing to determine which question you can actually answer.

This again has a lot of detail on it. Homogeneity of slopes is testing the hypothesis, ‘is there evidence for difference of rates.’ So in this case, it is saying our qualification for the site two rate equals site one rate. And this is done through a statistical significance evaluation. It is at the 5% level. It detects small differences between slopes. And it can be applied to data with high variability or low degradation rates.

What this can do though is you may have a statistically significant difference in rates for something that actually is not meaningful. And depending on having really good data, this will sometimes fail because we are picking up statistically significant differences. It can be applied to data with high variability or low degradation rates, so that is where the advantage comes in. It can pick up small differences.

The second one, the ratio of rates, and this is asking, ‘are they the same?’ And it is usually the ratio of the two rates, with a 90% confidence interval around those ratios. And so it passes – the ratio of the rates lies in this range. It gives a high degree of assurance that if there is a difference, that difference is small enough to be acceptable. And regarding the data generated with this, if there is a high assay variability – which we see in particular maybe with our ion exclusion type chromatography – or if the degradation rate is low, it could potentially fail this.

We have been using this two-stage approach. And I want to clarify that we only have to pass one of those two stages for it to pass comparability in this case. When we look at our historical information where we have applied both stages,




we see that 47 out of the total that we have looked at, 72, passed both the homogeneity of slopes criteria and the ratio test. 16 only passed the homogeneity of slopes. Seven only passed the ratio test. So you can see there is some opportunity here. And two actually failed both. I will be talking about both of those examples so you can see where the differences came from.

Overall, we found that this has been useful to include both, because we do not want to have a false failure in this. It does prompt us to make sure we understand what is going on and why we did not pass. But we do not consider it a failure of the overall comparability program.

Case Studies

Now I am going to go through three case studies of how we have applied this approach.

Case Study 1

The first was a liquid drug product transfer. The risk associated with the process of the tech transfer was assessed to be low. It was an internal transfer of a product that we had transferred multiple times. It is a fairly simple process in this case.

I am showing two attributes assessed by ion exchange chromatography. When you look at site one and site two, which I have designated here, looking at the degradation rates, you do not see a difference between the homogeneity of slopes. By our criteria, they passed. We saw that the material produced at site two is comparable to the material at site one. This, I think, was a very clean assessment. I would say it allowed us to proceed fairly quickly in this case.

Case Study �

This is where we have started having a lot of learnings about lyophilized drug product transfers. The risk of transferring the process was again assessed to be low. This was a product we had transferred twice before. We knew a lot about this product. Again, it was going into an internal site. The drug product batches met all of the release acceptance criteria.

With the stress study comparability part of the assessment, we saw that there were no new peaks. So the qualitative assessment looked very good. But when we looked at the degradation rates, we discovered that they were not comparable, using the two-stage model. This is a case where sometimes you look with your eye and you look with statistics, and sometimes you get a different answer. Site one is up here, and site two is down here.

For site one, we saw about an 8% change over six months. And for site two, about a 7% change over six months, which at least to your eye says those are pretty close. Those are the same. Where we failed was when we applied the statistics. It really came to the starting material and the values of the starting material.

You can see from this that when we applied the confidence interval for the ratio, we were outside the upper end in this case, and we were outside the upper end over here. When we looked at the P values we were not meeting the .05 number. So we did not meet either the stage one or the stage two criteria for comparability. And the overall results were failed because we did not pass either one of these.

I will say this gave us an opportunity for learning. So I do want to focus on this. We had different sources of our drug substance that went into these drug product lots. The different sources of drug substance demonstrated comparability. What changed was taking it into the lyophilized state. In that case we started picking up a difference in degradation that was fairly subtle related to the starting point here. There was quite a bit of scientific investigation that was performed…. We looked at development batches that were produced at site two compared to site one, and the development batches showed no difference.

This was an indication that it might not be site two that was causing this difference. And it really did point back to our starting point for this particular attribute that actually played a role in the overall assessment in the degradation. It was an unusual learning. We do learn quite a bit about our products, no matter how old they are. In this case, the


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observed rate differences were unrelated to the site change but were related to the starting level of the variant. We were ultimately able to say that comparability was demonstrated. The manufacturing of the drug product at site one and site two were comparable.

The differences that we were observing for all other attributes in the stress study criteria, and the scientific understanding of the rate difference from the stress study – because we did get that deep product knowledge – we could use to justify that although we saw a statistically different rate, that because we could explain why and because it was unrelated to the site transfer we could support comparability.

Case Study �

The third case study, again, is a lyophilized drug product transfer. This is a case where we failed comparability completely. This, again, was an older process that showed high variability with respect to moisture content. We were moving this process to one of our contract manufacturing organizations, and they had a similar product. Knowing that we did not have a robust process, we decided to employ the CMO’s more conservative drying cycle, thinking that it would produce better product for us.

So full-scale development runs performed at the CMO and the process characterization runs showed great initial results. Everything looked beautiful. We had our moisture content under control. However, we started to get an early indication of comparability from our stress degradation in the engineering runs. We still went forward as we were trying to understand the reason for that into qualification and registration batches at the CMO. And from those, and placing those on stress comparability, we also saw that we saw the same differences, which indeed led to failure.

Here there are very clean, unfortunately, results, because you can see there is a clear separation of site one and site two. This is looking at percent monomer stored for six months at 60° C. This, again, is a product that is highly stable at room temperature. And to be able to show differences, we actually have to take it to a fairly high temperature.

Homogeneity of slopes failed quite dramatically as did the ratio of the slopes. When you do the profile comparison, you can see that the site two actually is showing a new peak on the size exclusion chromatography that we do not see from site one.

This was a failure in many different ways. When we went back to look at the causes of the differences, it was related to the adjustment of the drying parameters. It was leading to a change of the lyophilized cake structure that ended up negatively impacting the stability.

When we were looking as part of the investigation to see if this was a meaningful change, we were actually able to go back and say we saw it at 60, we saw it at 45, we saw it at 30 – we had no confidence we could support expiration dating with this product. So we decided to stop the transfer at that point.

There is a lot of development work ongoing now to adjust the drying parameters. There is also a look at the equipment that the CMO is using, because that is one of the levers that we have to try to get our product back into something that is comparable.

Summary

So in summary, I would say that I hope I demonstrated to you that the stress studies do provide valuable information to support comparability. It is sensitive to minor differences. If we understand what those minor differences are, then it still gives us a path forward to show comparability in a much faster way than if we rely on real-time stability, which could take up to two or three years depending on the product.

With a stress study we can reduce the time depending on the product from two to six weeks to get this assessment done. It gives us a high degree of assurance that the material produced at the two sites is comparable and will meet its shelf life expectation.

The use of the two step approach we found provides an objective determination of comparability and really takes it




from what we call eye-balling the degradation rates down to something that is quite objective to determine whether the two are the same or not.

IPQ wishes to thank the following sponsors:

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Analytical Methods Handoff Pivotal to Successful Manufacturing Site Transfer, and Multiple Pitfalls Lurk, BCG Consultant Stresses at Latin America CMC Strategy ForumThe analytical methods handoff is pivotal to the overall success of a manufacturing process transfer from one location to another, and multiple pitfalls lurk, Biologics Consulting Group’s Christina Vessely cautioned at the 2015 Latin America CMC Strategy Forum organized by CASSS in Brasilia, Brazil in late August.

Vessely stressed that facility location transfers shed hard light on any weaknesses a manufacturer may have in understanding their analytical methods and manufacturing process and that these gaps can undermine the tech transfer, particularly given the analytical and process complexities in the biotech context.

The BCG consultant began her talk by highlighting the importance of establishing analytical comparability in relocating biotech manufacturing and advising on how firms can increase the probability of successfully dealing with the challenges involved.

She then explored the various problems that can and do surface in the analytics handoff in carrying out a process transfer plan – citing a case study of a transfer she was involved with from an internal site in Switzerland to an external CMO in the US. She concluded with a review of the key lessons learned.

Forum Includes Regulatory Agency Updates

The presentation by Vessely (included in full below) was one of three at a session of the Brasilia forum exploring the issues around technology transfer for biopharmaceuticals. Also presenting were Claudio Cabral from Brazil’s Instituto Butantan and Roche/Genentech Global Biologics Manufacturing and Technologies Head Mary Cromwell.

Cabral focused on the practical experience and lessons learned during the challenging and lengthy tech transfer of influenza vaccine production from Sanofi Pasteur to the Brazilian institute.

Motivating the transfer was the need for Brazil, like other developing countries, to have the ability to meet the vaccine demands created by influenza pandemics.

Cabral stressed the “solid partnership” that was required to transfer a complete complex production process and make possible the joint development of new competencies, improvements to the product, and further innovations.

Cromwell began by exploring the many reasons tech

transfers are necessary for a global company like Roche. She then focused, in particular, on the important role that stress studies play in helping address the comparability and stability concerns involved (see pp. 36-46).

Following the foreign CMC Strategy Forum pattern, the two-day Brasilia meeting included updates on the recent biotherapeutic regulatory trends in Latin America related to “convergence, predictability, transparency and priority reviews” from various of its agencies including those of Brazil, Peru, Chile, and Mexico. Updates on these issues were also provided by European and US regulators.

Along with tech transfer, other technical sessions addressed: ● cold chain management and qualification for biologicproduct transportation, and ● the characterization, control and regulation of protein glycosylation.

Lost in Translation

In her presentation on the analytical method issues that arise in transferring a manufacturing process from one location to another, BCG’s Vessely reviewed the technical challenges posed by equipment, facility, and infrastructure differences between the sites.

The key to a successful transfer is demonstrating the analytical comparability of the drug substance produced at each site, she stressed, pointing out that the need for clinical studies may hang in the balance.

Vessely explained the need to understand the status of the analytical method prior to the transfer and to have predetermined acceptance criteria based on this understanding. Increasing the probability of success is risk assessment prior to transfer, robustness studies, and setting up a transfer team that can engage in frequent communication with the other site.

A similar set of concerns needs to be addressed for the process transfer. Vessely highlighted the importance of communicating with the analytical experts to understand how method variability is at play in the process comparability assessment.

The BCG consultant then explored the problems that can arise in: ● the method transfer from acceptance criteria, SOPs, training, and environmental factors ● impurity profile




differences ● translation and communication, both of which need to be precise, and ● differences between internal processes and those at a CMO.

Moving from Switzerland to the Rockies

In Vessely’s case study of transferring a manufacturing process from an internal company facility in Switzerland to a CMO located in the Rocky Mountains in the US, the process transfer was complicated by quality system differences, while analytical comparability was complicated by the use of multiple laboratories at both locations for the performance of

in-process, release, and extended characterization testing.

Harmonization/understanding was lacking between the sites related to in-process methods, chromatogram integration, GMP robustness, culture, work habits and the openness to change.

The learnings, Vassely shared, included the importance of: ● risk assessments prior to starting the process transfer ●the communication of problems and the solutions that are already in the company domain ● upfront planning for how the changes between sites will be dealt with, and ● building a team that is “willing to communicate and willing to interact

BCG’S CHRISTINA VESSELY ON THE ANALYTICAL COMPONENT OF MANUFACTURING SITE TRANSFERS

At the Latin America CMC Strategy Forum heldin Brazil’s capitol city Brasilia in late August, Biologics Con-sulting Group’s Christina Vessely began her presentation by highlighting the importance of establishing analytical comparability in relocating biotech manufacturing and advising ob how firms can increase the probability of successfully dealing with the challenges involved. She then explored the various problems that can and do surface in the analytics handoff in carrying out a process transfer plan - citing a case study of a transfer she was involved with from an internal site in Switzerland to an external CMO in the U.S. She concluded with a review of the key lessons learned.

I am not going to go into this slide [on ICH Q5E expectations for comparability exercises] in a lot of detail since Mary [Cromwell] talked briefly about it. But I did really want to point out the last bullet here, which is that analytical comparability is very important because it is ultimately used to determine to some degree whether or not you are going to need to do confirmatory non-clinical or clinical studies to support a manufacturing change or a process transfer.

Analytical Comparability and Method Transfer

I want to go through the steps to establish comparability. The first step is transferring your analytical methods to the new site. This includes both your in-process and your release methods. Then, of course, there is the manufacturing process transfer itself, which is followed by the formal comparability exercise.

As Mary kind of pointed out, we do need to have predefined acceptance criteria for that comparability exercise. You really need to know your product – know what the critical quality attributes are that you need to follow during that transfer. And, as Mary also discussed, you are not just looking at your product quality at release. You are looking also at stability and forced degradation studies.

A couple of questions you want to ask yourself as you start this method transfer process:

The first question is, what is the status of my analytical method prior to the transfer?

● Is this a validated method?

● Is this a qualified method?

Depending on the stage of product development you might have limited experience with some of your analytical methods, which is going to complicate the question of, have I adequately transferred this


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analytical method?

● Have you performed forced degradation studies on the analytical method?

● Are you confident that your method is going to show you degradation products if they exist in the product?

● Ultimately, how are you going to know if your method transfer was successful?

● Again, this comes down to having predetermined acceptance criteria, which in many cases are going to be based on your qualification or validation data if you have them.

How do you increase the probability of success for your analytical method transfer?

● Risk assessments are a very good starting point. You need to assess all the important parameters of yourmethod. What are the instruments like at the sending and the receiving sites? Do you have the same type of HPLCs? What is the availability in your key regions? Are there going to be reagent differences as you look at one region versus another?

● Have you performed robustness studies on your assay? Do you know what the sensitive points are on themethod? And can you put more attention to those in the transfer?

● Another key point is setting up a transfer team. That does not necessarily mean 30 people at each site toaccomplish the transfer. It is really dependent on how many methods you are transferring. If it is only a few methods, it might just be one person at each site. But one of the keys in the transfer team is having an open door to regular and frequent communication. For some of your more complicated methods, there is a lot of value in having a face-to-face transfer exercise, because there are a lot of methods that are sensitive to laboratory technique. With an HPLC assay as an example, there can be a lot of variability from one analyst to another in the integration of your chromatograms.

Manufacturing Process Transfer

With respect to the manufacturing process, you would also perform a similar risk assessment to make sure that you have a good fit for the facility that you are transferring to. It is analogous to the analytical method transfer in that you are looking for similarity of equipment, availability of the key materials, and just making sure that the facility has the appropriate infrastructure in place to support the transfer.

You are asking a lot of the same questions that you do with your analytical transfer:

What is the status of the process?

● Is it validated?

● Do you really understand what your operating ranges are?

● And can you stay within those ranges?

How do you define those critical quality attributes?

● Do you really understand which impurities are important to overall product quality and safety?

● What levels have been established clinically? So if you go outside of that normal range, have you done that




historically in your early clinical studies? Or is that something that you cannot support in terms of safety?

● This is a point that seems like it sometimes gets overlooked: There needs to be very good communicationbetween the process engineers and the analytical people to make sure that there is a thorough understanding of the methods in terms of method variability, and understanding what level of difference you might see in your analytical results that would be considered significant vs. just method variability.

Formal Comparability Exercise

As you complete the transfer, the final step is the formal comparability exercise. You really need to have a plan for how you are going to accomplish this. You need to have a determination of how many lots are going to be included.

This also might be dependent on the stage of your product. If you are at a very early stage, you might only have one or two lots available from your originating site prior to that transfer. So when you are looking at a retrospective comparison for some of your data, you might have a very limited data set to choose from.

There is also the question of whether you are going to do retrospective analysis vs. side-by-side analysis.

For a lot of your in-process data, you do not really have an opportunity to test things side-by-side. It is really going to be a retrospective assessment, which makes it very critical that you have adequately transferred that analytical method and that you know that the impurity profile you are seeing is consistent between the sites for the same material. Also in this retrospective comparison you are going to put a lot more attention onto your critical quality attributes.

Going into the release testing of the materials, you have a choice between retrospective versus a side-by-side analysis at this point. A retrospective is perfectly adequate for many of your simpler methods – pH, concentration determination, and some of the simple methods where you do not really need to do side-by-side. Where you really gain value in that side-by-side analysis is with your purity and impurity methods.

Mary showed a good example of a profile for one of their methods that had a lot of peaks that you are looking at. If you are analyzing three batches within the same analytical run, you can overlay those same data and you can really see if you are seeing peaks coming in the same location. Are they the same order of magnitude?

If you look at materials that have been tested at different times, each run is going to have a little bit different run time, different age of the column. It might become very complicated to determine if those truly are comparable impurity profiles.

Another part of your comparability exercise is your extended characterization studies. This is beyond the release methods. You really need to look at your product to determine what methods are needed to support claims of comparability. And there is some difference in those methods based on the type of product – for example, glycosylation profile is not important for an E. coli-derived protein.

Again, how are you defining those predefined acceptance criteria? What is your basis for those criteria? There are really two parts to that that are very important:

● The first one is evaluation of your historical data. And as I said earlier, you might have a limited amount ofhistorical data, but you need to understand what the ranges are that you typically see with the original process.

● Then there is the evaluation of the method capability and variability. If you have a method that gives you aprecision of 5%, you probably do not want to set an acceptance criteria on your transfer of 2%. You are likely to fail that.

There is the also the evaluation as Mary discussed, looking at the quality at release in stability and forced degradation studies, looking for comparable trends. And you need to look to see if you have new impurities or different degradation pathways.


SEPTEMBER 2015 �1 ......... ....


I will speak briefly about reference materials. Your reference material is your bridge to the past. It is one way to establish that tie between the original process and the transferred process. But it also is a valuable tool for knowing whether your methods are operating properly. For example, if you suddenly lose an impurity species in your product, you might be happy about that initially, but if you have also lost it from your reference standard, you know your method is not performing adequately.

These are also good for determining if you have method drift due to changes in reagents, chromatography columns, etc. It also gives you an opportunity to investigate and to better understand some of the results that you might see that are not expected.

Method Transfer Problems

Alright, so we have our process transfer plan. What could possibly go wrong? There are a lot of things that can go wrong.

Method Transfer Failure

First of all, you can fail your method transfer. There are a couple of things that happen with method transfers. The first is that depending on the data that you had prior to the transfer, you might set your acceptance criteria too tight or too narrow. If you do not really have intermediate precision data established, you do not know how much variability you should expect from one analyst to another.

Inadequate SOPs: When you develop a method you tend to be very close to that method. You understand it very well. And there are a lot of things that you communicate during training of your analysts at your site that do not necessarily make it into the SOP. So the analyst at the receiving site might not have adequate information to perform the method successfully.

Training: If you are not familiar with the method, it may perform differently in your hands.

There are also environmental factors. As an example, I am from Colorado. Colorado is very dry and we get very cold in the winter. If you were to perform an assay in our laboratory and you tried to transfer that assay to Texas, you might see very significant differences. As an example, even within one of our laboratories, we had one bench of HPLCs that was close to a window. We get a lot of sunshine in Colorado. That part of the room ended up being several degrees warmer than the other half of the room. A lot of the methods that we were running at the time were being run under ambient conditions. And even within that laboratory, ambient had a different meaning.

Impurity Profile Differences

When you are actually looking at the product there may be some real differences in your impurity profiles.

If you transfer a fermentation from one fermenter to another and there is a different geometry and different size, you may have variability of the mass transfer and some of the other parameters that you are seeing.

You might have differences in your reagents based on what is available in different regions.

I think maybe the key is if that you do not have that adequate understanding of your process variability prior to that transfer, and understand also how analytical method variability plays into the variability you see in you process results, that can really impact your ability to successfully transfer the process.

The batch records used for your manufacturing process are similar to your SOPs for your analytical methods in that if you do not have sufficient information in there for them to be performed successfully, you have a low probability of a successful transfer.

Translation and Communication

I would like to explore the concept of ‘lost in translation.’ This is something that can be especially problematic when




you are transferring from one region to another. It is very important on these transfers that all of the batch records, SOPs, and all of your documentation is transferred into the native language of the operators who are going to be performing the method and the functions.

This really requires a formal GMP translation exercise – not just the use of Google Translator. Even after that GMP translation has been performed it is important that you have discussions between the operators from each site, or supervisors, to make sure that what is actually in those batch records is correctly translated and that there is not something that has been lost.

There is value in these cases of the operators from the originating site observing the performance at the transfer site to make sure that something was not missed there.

Precise communication is important. As Americans, we use a lot of [jargon]. And what we have learned in visiting Switzerland on several occasions is that some of the things that we say all the time either have no meaning or they mean something completely different in a difference culture. So it is important that you understand not just what you are talking about, but what you actually are saying.

Continuous communication is important. Even after you think you have successfully transferred the process, it is important to make sure that you have access to the people who have more experience with the process.

Internal vs. External Transfers

Internal versus external: When you are transferring a method that you had at an internal company site to a CMO, you may find that there are different processes in place at the CMO. It is important before you perform that transfer to understand some simple things like, how are deviations handled at the CMO? How much control do you have over activities and decisions?

Here is another example: Our originating site had historically used reverse phase HPLC to do their quantitation of yields throughout their process, upstream and downstream. They did all of their process validation using reverse phase. And it was the decision that it was going to be their assay moving forward.

When we transferred this to the CMO, the CMO said ‘no, we are not going to do reverse phase, we are going to do UV.’ That is relatively simple. We are just talking about protein concentration, so you can justify that difference. But depending on how you are doing the analysis, you might see slight differences in your yield depending on if you are looking at total protein concentration or if you are looking at your main peak, etc. It is important to understand those activities.

How are the laboratory investigations performed at your CMO or CRO, and to what level? To give a kind of horrible example, we were working with a CMO/CRO on some stability studies and they had an apparent failure on a stability-indicating method. They did an internal investigation and informed us after the fact that it was a stability failure.

Of course, we were concerned by this. It was something we were not expecting. We finally were able to get the raw data, the chromatograms, and take a look at them. We saw the appearance of a very large peak in one of their assays. On the surface, it did look like a true stability failure. But we went back and looked at the reference standards and the

blanks, and that large peak was in all of those also.

So they did not, in my opinion, perform an adequate investigation. But ultimately as the owner of the product, we had a lot more work to do to negate that stability failure that they had reported. It was all very explainable, but it took time and it took a lot of paperwork to get over that process.

Process Transfer Case Study

I am going to talk in a little bit more detail about a particular case study where we were transferring a process from an internal company site in Switzerland to an external site in the US. This was in an effort to increase our manufacturing


SEPTEMBER 2015 �� ......... ....


capacity. The intent at the time was that both sites would continue manufacturing product. Due to the distance between the sites, it was not really feasible to have a central location for all of our analytical testing.

What we found was that we lacked harmonization between the sites in a number of areas. The first was our compendial methods, which is not necessarily problematic. But it became an issue when we were working on our BLA, because we determined that some of our microbial methods were different between the different sites. We needed to make sure we had adequately covered that in the BLA process.

As I mentioned earlier, we had differences in some of our in-process methods. So again, that became a BLA issue more than anything else, to make sure we had adequately described what we were doing.

We found differences in our integration. So you can see in this chromatogram that in this particular analysis the integration cuts this shoulder – on both sides we cut both the early shoulder and the late shoulder. And they really quantitated based on that main peak.

The other site did not do that – they calculated it based on the entire peak. This particular chromatogram is not necessarily a worst case. It does not look that bad. But you can imagine that for something with higher levels of impurity, higher levels of shoulders, that is really going to impact that yield calculation and make it look like there is a difference when there may not be.

I think that the most frustrating aspect of this transfer is that we had inadequate change control systems. What we are finding is that the modifications to analytical methods would occur at the site level, and were not necessarily communicated up to regulatory and then back down across the different sites. For this particular product, I believe we had somewhere on the order of four different analytical sites that were performing assays. You can see how very quickly if a site is making a change to a method that this is going to ultimately result in different methods at different sites. It is going to be very difficult to reconcile later.

In addition to the GMP sites, we also had non-GMP sites involved who were working on process improvements with methods that were ultimately out-of-date and not as robust and not as meaningful.

There were cultural differences that we did not anticipate. For example, we made plans, we had five contractors from the US who were planning to attend the site for a particular day – a Monday in September. It happened to be a holiday that we do not celebrate in the US. So as a result we lost an entire day of contractor time because they were not allowed to enter the site.

Differences in work habits. This seems silly, but as Americans we often work through lunch. In this particular culture in Switzerland, it was frowned upon and we were laughed at. I see you are laughing at me now for this.

Then are there a maximum number of hours that an operator can work per week. In the US, we pay overtime, so we do not worry too much about it. But in other areas that is not necessarily allowed on a long-term basis.

There was also resistance to change. There were different requirements in the different regions. And there was a lack of understanding that since we were transferring something that was ultimately going to be approved in the US that we had to meet all of the US standards, not just the standards that they were historically used to meeting.

Lessons Learned and Conclusions

In terms of lessons learned, risk assessments are very important. It is important you do those prior to starting your process transfer. They will help you to evaluate what your potential problems are before you get into the middle of them.

Communication: You cannot communicate enough. You cannot over communicate in the transfer. You need to have rapid reporting of problems as they occur, because you might find that someone at the originating site has already had that problem and already knows the solution. Do not spend a lot of time trying to solve a problem that may have




already been solved historically.

Your systems need to set up for success. You need to have a plan upfront for how you are going to deal with changes as they occur between the sites.

You need to build a team that is willing to communicate and willing to interact in positive ways. And people need to be included in discussions that should be part of those discussions.

In conclusion, it is pretty common that you are going to have to transfer a process somewhere during your development lifecycle or even post-marketing. It is important to establish your analytical comparability in order to have a successful transfer. And I do not think I can stress enough that communication is your key to that successful transfer.

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Updates in Brief

CMC/REVIEWWoodcock at Congress on Biosimilars

In mid-September, Center for Drug Evaluation and Research (CDER) Director Janet Woodcock testified as the sole witness in front of the Senate Subcommittee on Primary Health and Retirement Security regarding FDA’s progress on guidances for biosimilars. Woodcock maintained that the scientific framework must be “bulletproof” to ensure that there are no problems with “the first biosimilars out of the block.” She referenced three FDA biosimilar guidances finalized earlier this year (IPQ “Monthly Update” April/May 2015, p. 57) and pointed to a guidance that is expected to be released by year-end on “Statistical Approaches to Evaluation of Analytical Similarity Data to Support a Demonstration of Biosimilarity,” which she characterized as “the third most important guidance document” after labeling and interchangeability. Woodcock also told the committee that she cannot provide specific dates on when guidance documents will be released or finalized, noting that the process is “complicated.” To see a video of the hearing, click here.

New OPQ Director

Center for Drug Evaluation and Research (CDER) director Janet Woodcock announced the appointment of former Novartis Global R&D VP Michael Kopcha as the “permanent” director of CDER’s Office of Pharmaceutical Quality (OPQ). Kopcha has 25 years of experience in the pharma industry, and worked at J&J prior to going to Novartis. He will start his position in November pending ethics clearance. [For more on OPQ and the role Woodcock played in creating it see IPQ “Monthly Update” April/May 2015, pp. 3-13.]

Draft Addendum to ICH M7

In late September, FDA announced the availability of a draft addendum (R1) to ICH M7 on “Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk; Application of the Principles of the ICH M7 Guidance to Calculation of Compound-Specific Acceptable Intakes.” The draft guidance is an addendum to the ICH M7 guidance (IPQ “Monthly Update” April/May 2015, p. 58) that provides guidance on acceptable intake limits derived for some chemicals that are considered to be mutagens and carcinogens. The chemicals were selected because “they are commonly used in pharmaceutical manufacturing or are useful in illustrating the principles for deriving compound-specific intakes as described in ICH M7.” Comments are due by November 27.

Final Guidance on Generic Drug Controlled Correspondence

In late September, FDA issued a final guidance on “Controlled Correspondence Related to Generic Drug Development,” that provides information regarding the process by which generic drug manufacturers and related industry – for example, contract research organizations (CROs), active pharmaceutical ingredient (API) manufacturers, and excipient manufacturers – can submit correspondence to FDA requesting information related to generic drug development. The 15-page guidance includes an introduction and background sections, and sections on the definition and structure of controlled correspondences, how to submit them, and communications between the agency and companies submitting the correspondences. It is essentially identical to the 2014 draft, with: ● additional explanatory information ● a description of how to submit information to FDA’s Inactive Ingredient Database, and ● a description of enhanced communication to requestors regarding the status of their controlled correspondence. The guidance is one of several put in place to help implement the 2012 Generic Drug User Fee Amendment (GDUFA) (IPQ “Monthly Update” September 2012, pp. 44-45). OGD’s draft guidance on controlled correspondence followed in the wake of a sharp rise in those correspondences – specifically the ones containing chemistry questions (IPQ “Monthly Update” June 2014, pp. 11-13).

Final Guidance on Generic Drug Physical Attributes

In June, FDA released a final guidance on “Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules.” The guidance puts forth agency recommendations that generic drugs should be as similar as possible to the reference listed drug (RLD) they may be substituted for in terms of size, shape, color, smell, and other physical attributes so as to not affect patient compliance or medication errors. The final guidance is substantially the same as the 2013 draft, with only minor editorial changes. It applies to abbreviated new drug applications, but not to products already approved for marketing. In its comments on the 2013 draft,

UNITED STATES

http://www.ipqpubs.com/issues/ipq-monthly-update-aprilmay-2015/

http://www.help.senate.gov/hearings/biosimilar-implementation-a-progress-report-from-fda




http://www.ipqpubs.com/wp-content/uploads/2015/10/OPQ_director.pdf

https://www.federalregister.gov/articles/2015/09/28/2015-24510/m7r1-addendum-to-ich-m7-international-conference-on-harmonisation-draft-guidance-for-industry

http://www.ipqpubs.com/wp-content/uploads/2015/10/M7_R1_09.2015.pdf

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM411478.pdf

http://www.ipqpubs.com/issues/ipq-monthly-update-september-2012/

http://www.ipqpubs.com/issues/ipq-monthly-update-september-2012/

http://www.ipqpubs.com/issues/ipq-monthly-update-june-2014/



C:\Users\Jerry\Downloads\GPhA_Comments_on_Docket_FDA-2013-N-1434-0001.pdf




the Generic Pharmaceutical Association (GPhA) expressed concerns that it has reiterated in a letter to FDA on the final guidance. The association maintains that the guidance “imposes arbitrary requirements even in the absence of known safety issues.” It further maintains that in drafting the Drug Price Competition and Patent Term Restoration Act of 1984 – better known as the Hatch Waxman Amendment – Congress took “special care” to include, in the statute, “the essential requirements, and to preclude non-essential requirements that would provide unnecessary barriers to generic competition.” It concludes that “the premise of the guidance, that generic drugs must mimic the reference listed drug in size and shape, has no basis in law.”introduction and background sections, and sections on the definition and structure of controlled correspondences, how to

GMP/INSPECTION

Final Rule on Drug Destruction

FDA announced in the Federal Register its implementation of a final rule on destruction of drugs that have been refused entry into the US. The rule, a part of Title VII of the 2012 FDA Safety and Innovation Act (FDASIA), provides FDA authority to destroy imported drugs valued at $2,500 or less that are adulterated, misbranded, or counterfeit drug and have been refused admission into the US (IPQ “Monthly Update” October 2012, pp. 4-11). The agency notes in the announcement that the public consultation on the rule (IPQ “Monthly Update” May 2014, p. 29) received 22 comments, but that it did “not make any changes to the regulatory language included in the proposed rule.” A due process provision allows for the destruction after notice to the owner and the opportunity to provide testimony opposing the destruction. The owner or consignee may be liable for the costs of storage and disposal. (For more of IPQ’s extensive coverage of FDASIA, click here.)

Overseas Offices

In a blog post, FDA Deputy Commissioner for Global Regulatory Operations and Policy Howard Sklamberg announced new leadership for its overseas offices and touted accomplishments of those offices to date. Replacing current office directors who “have moved on to other opportunities” are: ● Leigh Verbois (China) ● Donald Prater (Europe) ● Mathew Thomas (India), and ● Edmundo Garcia, Director, and Capt. Philip Budashewitz, Deputy Director (Latin America). Accomplishments cited include:● working with Mexican regulators to follow up on FDA inspection results and take immediate actions against firms andproducts that violate U.S. and Mexican law ● an increase in the number of FDA inspectors in China, and ● the key role the European Office played in the Mutual Reliance Initiative (MRI). The FD-EU initiative involves evaluating the regulatory frameworks for inspections of manufacturers of human pharmaceuticals to determine if the US and EU can rely on each other’s inspectional information.

Sun Drug Approval Rescinded

In late September, FDA sent Sun Pharma a Complete Response letter (CRL) rescinding its March approval of a New Drug Application (NDA) for Elepsia XR levetiracetam ER tabs, according to Reuters. In the letter, FDA explained that the compliance status of the manufacturing facility in Halol, India was not acceptable on the date of approval, leading to the denial of the application. Levetiracetam is an antiepileptic drug (AED) indicated for adjunctive therapy in the treatment of partial onset seizures in patients 12 years of age and older with epilepsy. In May 2014, FDA issued a warning letter to Sun Pharmaceuticals in the wake of a November 2013 inspection that found data integrity problems at the firm’s Karkhadi, India API facility, which resulted in it being placed on FDA’s import alert list two months earlier. Integrity concerns cited at the facility included: lack of raw data, “unofficial testing” of samples, and failure to identify raw materials. Earlier in 2014, Sun bought Ranbaxy, which had also been enmeshed in data integrity problems with the agency. [See IPQ “Monthly Update” March/April 2014, pp. 19-29 and July/Aug. 2013, pp. 2-8 for more on FDA’s findings of data integrity problems in India.]

API from India’s Polydrug Banned

In mid-September, FDA initiated an import alert against Indian active pharmaceutical ingredient (API) manufacturer Polydrug Labs located in Mumbai, citing GMP concerns. The same firm was inspected by EU authorities earlier this year, also leading to an import ban in June (IPQ “Monthly Update” June 2015, p. 31) citing GMP and data integrity concerns. Also in June, Health Canada requested that Canadian importers voluntarily quarantine drug products with APIs “manufactured or tested by” Polydrug, citing “recent findings from trusted regulatory partners that raised concerns about the reliability of data generated at the site.”

Imports from Canadian Company CMI Banned

In late September, FDA banned Canada’s Cosmetic Manufacturers Inc. (CMI) from importing its products –cosmeceuticals, nutraceuticals and pharmaceuticals, which include a digestive enzyme therapy and sunscreen products – into the U.S. The import alert cites GMP issues as the reason for the ban. A 2013 warning letter to the firm cites issues with identity tests on incoming raw

http://www.regulations.gov/#!documentDetail;D=FDA-2013-N-1434-0032

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http://www.ipqpubs.com/issues/ipq-monthly-update-october-2012/

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http://www.ipqpubs.com/?s=FDASIA&submit.x=17&submit.y=8

http://blogs.fda.gov/fdavoice/index.php/2015/09/welcoming-fdas-new-overseas-leaders-fdas-foreign-posts-provide-a-vital-resource-for-consumer-protection/?source=govdelivery&utm_medium=email&utm_source=govdelivery

http://www.reuters.com/article/2015/09/26/us-india-sun-pharma-idUSKCN0RQ04T20150926?feedType=RSS&feedName=healthNews

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm397054.htm

http://www.ipqpubs.com/issues/ipq-monthly-update-marchapril/

http://www.ipqpubs.com/issues/ipq-monthly-update-%E2%80%93-julyaugust-2013/

http://www.ipqpubs.com/issues/ipq-monthly-update-june-2015/

http://www.accessdata.fda.gov/cms_ia/importalert_189.html?source=govdelivery&utm_medium=email&utm_source=govdelivery

http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2015/53932a-eng.php

http://www.accessdata.fda.gov/cms_ia/importalert_189.html

http://www.accessdata.fda.gov/cms_ia/importalert_189.html



SEPTEMBER 2015 �� ......... ....


Impax Warning Letter Resolution

After an FDA inspection earlier this year, Impax Labs announced in a press release in early September that it has received written notice from FDA verifying that the company has successfully addressed all items raised by the agency in a May 2011 warning letter relating to its Hayward, California manufacturing facility. Impax is a specialty pharmaceutical company that develops controlled-release and specialty generics in addition to central nervous system disorder branded products.

www.usp.org

2nd Excipient Workshop: Focus on Excipient Quality, Compendial Testing, and Regulatory ImpactNovember 17-18, 2015 - November 19, 2015

Adulteration and Fraud in Food Ingredients and Dietary SupplementsDecember 3, 2015 - December 4, 2015

Upcoming Workshops:

http://investors.impaxlabs.com/Media-Center/Press-Releases/Press-Release-Details/2015/Impax-Announces-Resolution-of-FDA-Warning-Letter-Related-to-its-Hayward-Manufacturing-Facility/default.aspx

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm258197.htm

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm258197.htm

http://www.usp.org/meetings-courses/workshops/adulteration-and-fraud-food-ingredients-and-dietary-supplements

http://www.usp.org

http://www.usp.org/meetings-courses/workshops/2nd-excipient-workshop-focus-excipient-quality-compendial-testing-and-regulatory-impact

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We support our suppliers and colleagues who share our support of Rx-360 and its critical mission to protect patient safety. And, recognizing the power of leadership by example, we

invite others who share our patient safety goals to join us in this important endeavor.

Wes SchmidtVP, Quality Systems

AbbVie

William ReisVP, Global Strategic Sourcing

Amgen Inc.

Martin VanTriesteSVP QualityAmgen Inc.

Gary A. BakerVP, QARA

Ash Stevens, Inc.

Ashley ReadshawChief Procurement Offi cer

Astrazeneca

Peng ZhienPresidentAurisco

Richard M SiberskiGlobal Director of Quality

Avantor Performance Materials

Jaspreet GillVP, Global Quality & ComplianceBaxter Healthcare Corporation

Dr. Paul Heiden SVP QHSE

Bayer HealthCare

Richard SpoorSVP ProcurementBayer HealthCare

Debra KatterVP, Corporate Quality

Bend Research

Melissa Stoutt SeymourSr. Director, Corporate Quality

Biogen Idec, Inc.

Robert PantanoSVP, Warehouse Operations and

Operational ExcellenceCardinal Health

John NicolsPresident and CEO

Codexis, Inc.

Allen WelsherGlobal Head QA

Daiichi Sankyo Co., Ltd.

Jennifer Finnegan McCafferty

VP External QualityGlaxoSmithKline

Luisa PauloCompliance Director

Hovione

Vincent AntleSr. Director of Technical Operations and Quality

AssuranceLigand Pharmaceuticals, Inc.

Robert NassVP Quality and Regulatory

Management Merck Millipore Merck KGaA

Matt AndersonVP Quality

Merz North America, Inc.

Patricia M. LatzoSVP Global Quality and Strategic

SourcingMylan Inc.

Michael CohenManaging Director

Myoderm

Michael HoffmanVP Global Procurement

Pfi zer Inc.

Heiko HackelVP Global Sourcing

Sartorius

Thomas PaustVP Supply Chain Management

Sartorius

Tom BeilVP, Quality and Regulatory

AffairsSigma-Aldrich

Tom TynerVP Quality & Technical Service

Spectrum Chemicals and Laboratory Products

Steve FeldmanVP Quality & Regulatory Affairs

Temptime Corporation

Angélique KlootwijkDirector Quality Management &

Quality AssuranceVWR International

Pfi zer Inc.

Heiko HackelVP Global SourcingVP Global Sourcing

Robert Pantano

Thomas Paust

Richard M Siberski Melissa Stoutt Seymour

GlaxoSmithKline

Luisa PauloCompliance Director

William Reis

Robert NassRobert NassVP Quality and Regulatory

Management Merck Millipore

Wes Schmidt

Tom BeilDebra Katter

Allen Welsher

Hovione

Vincent Antle

Patricia M. Latzo

Ashley Readshaw

Temptime Corporation

Angélique KlootwijkDirector Quality Management & Director Quality Management &

Michael Cohen

Peng ZhienPresidentAurisco

Martin VanTriesteSVP Quality

Myoderm

John Nicols

Sigma-Aldrich

Tom TynerVP Quality & Technical Service

Spectrum Chemicals and

Gary A. BakerVP, QARA

Ash Stevens, Inc.

Jaspreet Gill

Jennifer Finnegan McCafferty






EUROPE

CMC/REVIEW

Pre-Authorization Procedural Advice

EMA has released an update to its “pre-authorization procedural advice for users of the centralized procedure.” The 153-page guideline, meant to be read in conjunction with the 2005 “Rules governing medicinal products in the European Union”, Volume 2A, Notice to Applicants, is presented in a Q&A format with 66 questions, 22 of which have been added in this update. The ques-tions and answers guide applicants through determining if the centralized procedure can be used, what should be submitted, the applicable timetables, fees, and other relevant information.

CEP Requirement Revision

In September, the European Directorate for the Quality of Medicines (EDQM) published a revision to its certificate of suitability (CEP) requirements in a policy document titled “Content of the dossier for chemical purity and microbiological quality.” The document is meant to provide guidelines for CEP applicants to aid them in preparing the application and compiling the relevant supporting documents. It takes into account regulatory developments in Europe reflected in ICH, EMA, and Ph.Eur monographs since the previous revision of the guideline. The effective date is September 1, 2015, and is applicable to new submissions as well as those that have already been submitted but not yet approved. The majority of the changes were made in Module 3, including how to submit: ● different grades of active ingredient ● different production sites and manufacturing processes ● a justification for the selection of the starting material ● validation data for manufacturing sterile substances, and ● impurities testing, including for reagents, catalysts, solvents, and by-products.

EDQM Technical Guide

In a press release on the 152nd European Pharmacopeial Coommission meeting last summer, EDQM announced an update to its Technical Guide for the elaboration of monographs. The guide provides instructions for the drafting of monographs and for the transposition of analytical techniques and parameters into a pharmacopoeial method. Use of the guide, EDQM maintains “helps to ensure a high level of harmonization throughout the texts of the Ph. Eur.”

GMP/INSPECTION

EU GMP Implementing Act

The EU Commission has published a new public consultation on an “Implementing Act on Principles and guidelines on good manufacturing practices for medicinal products for human use.” The Delegated Act is procedural in nature, made necessary due to the repeal of an earlier directive that left investigational medicinal products without a directive to follow. The Commission notes that “as good manufacturing practice for medicinal products for human use already exists and is generally well-functioning, there is no need to reinvent the wheel and therefore, this consultation document carries over the majority of the principles and guidance set out in Directive 2003/94/EC relating to medicinal products for human use.”

EU RTR Guideline

The European Commission has released a draft update to EU GMP Annex 17 on real-time-release (RTR) testing, following up on a concept paper released in late 2012 (IPQ “Monthly Update” Jan./Feb. 2013, pp. 31-41). The previous 2002 guideline focused solely on the application of parametric release for the routine release of terminally sterilized products. However, advances in the application of process analytical technology (PAT), quality by design (QbD) and quality risk management (QRM) principles to pharmaceutical development and manufacturing “have shown that appropriate combination of process controls together with timely monitoring and verification of pre-established material attributes provides greater assurance of product quality than fin-ished product testing (conventionally regarded as the end-product testing) alone,” the guideline states. It is also being revised to bring it into line with ICH Q8, Q9, Q10 and Q11. The public comment period extends until December 11.

http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004069.pdf

http://ec.europa.eu/health/files/eudralex/vol-2/a/vol2a_chap1_2005-11_en.pdf

https://www.edqm.eu/sites/default/files/cep_content_of_the_dossier_for_chemical_purity_microbiological_quality_september_2015.pdf

https://www.edqm.eu/sites/default/files/press_release_152nd_session_of_the_european_pharmacopoeia_june_2015.pdf

https://www.edqm.eu/sites/default/files/technical_guide_for_the_elaboration_of_monographs_7th_edition_2015.pdf

http://ec.europa.eu/health/human-use/quality/pc_quality/consultation_document_ia_gmp_for_finished_mp_rev_180815_en.pdf

http://ec.europa.eu/health/human-use/quality/pc_quality/consultation_document_annex_17.pdf

http://www.ipqpubs.com/issues/ipq-monthly-update-jan-feb-2013/


SEPTEMBER 2015 �� ......... ....


EMA and WHO Information Sharing

The European Commission and the European Medicines Agency (EMA) announced an agreement with the World Health Or-ganization (WHO) to share certain non-public information on the safety, quality and efficacy of medicines already authorized or under review in the European Union (EU), or pre-qualified or under review by WHO. Included in the information sharing will be data related to inspections and manufacturing facilities. The agreement became effective on September 1.

APIC ICH Q7 Guide Revision

The Active Pharmaceutical Ingredients Committee (APIC) has revised its “how to do” document that aims to help API manu-facturers comply with ICH Q7. The latest revision, Version 8, released in August, updates the 2012 revision with changes to chapters 10 on “Storage and Distribution,” 11 on “Laboratory Controls,” 12 on “Validation,” and 15 on “Complaints and Recalls.” Key changes include: ● in chapter 10 on storage and distribution – the importance of controlling the temperature in warehouses accounting for seasonal temperature changes; how to perform temperature mapping; the necessity of physical separation be-tween released and returned materials; and the importance of quality agreements with logistics companies ● in chapter 11 on lab controls – the importance of validating analytical methods and data integrity; the need for an SOP for producing data averages including rounding rules; the addition of ICH M7 and Q3D guideline references; and guidance on FDA expectations for imported APIs ● in chapter 12 on validation – how to handle critical quality attributes (CQAs) with references to ICH, FDA, and EMA guidelines; the importance of pre-defining and justifying the number of validation batches; an emphasis that CQAs in validation batches must be comparable or better than those in the reference batches; and that the selection criteria for reference batches must be justified ● in chapter 15 on complaints and recalls – the necessity of investigating batches related to those being recalled; defin-ing a timeframe for closing complaint investigations; and how recalls of APIs are conducted in conjunction with the dosage form manufacturer and local health authorities.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2015/09/news_detail_002396.jsp&mid=WC0b01ac058004d5c1

http://apic.cefic.org/pub/Howtodo-ICHQ7_August2015_version8.pdf


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INTERNATIONAL

GMP/INSPECTION

WHO Notice of Concern to India’s Svizera Labs

In early September, the World Health Organization issued a “Notice of Concern” to Mumbai-based Svizera Labs that details “major” and “critical” deviations from WHO GMP standards found during a June 2015 inspection. The inspection was a pre-qualification audit by WHO of the firm as a supplier of tuberculosis medicines to the Stop TB Partnership program. The deficiencies cited regarded: ● adequacy of dissolution testing and possible manipulation of dissolution data ● data integrity and the ability to retrieve raw data ● conduct of stability testing ● maintenance of equipment log records ● contamination controls ● potential falsification of analytical data ● food trash and manufacturing waste in a room directly adjacent to a manufacturing area ● a lack of gowning instructions for production operators ● adequacy and completeness of in-process control records, and ● appropriate protection of product during packaging.

Health Canada Lifts Ban on Apotex Products

Health Canada announced that it has lifted its ban on generic drug products from two Apotex plants in India, with the conditions that the products be retested at an Apotex facility in Canada before entering the Canadian market and that plant management keep the agency apprised of failing test results and their investigations. A 2014 FDA ban on products from the two facilities in the wake of a 2013 warning letter (IPQ “Monthly Update” March/April 2014, pp. 19-29) remains in place. Apotex received a second FDA warning letter in early 2015 at a different facility in India (IPQ “Monthly Update” February 2015, p.51).

India Strengthens State Drug Regulation

India’s Central Drug Standards Control Organization (CDSCO) announced that it intends to improve the regulation of drugs manufactured in its country by investing the equivalent of US $129 million to improve the effectiveness of its state drug regula-tory counterparts. Some funds will also need to be supplied by the state agencies. In a “memorandum of understanding” (MOU) with the state agencies, CDSCO notes the following areas of deficiency that will be targeted: ● inadequate or weak drug control infrastructure at the state level ● inadequate drug testing facilities ● non-uniformity of enforcement of law and rules ● lack of training to regulatory officials ● lack of databases, and ● inadequate IT services.

http://apps.who.int/prequal/info_applicants/NOC/2015/NOC_Svizera02September2015.pdf

http://www.firstwordpharma.com/node/1311696#axzz3l6CAxSks

http://www.ipqpubs.com/issues/ipq-monthly-update-marchapril/

http://www.ipqpubs.com/issues/ipq-monthly-update-januaryfebruary-2015

http://www.cdsco.nic.in/writereaddata/NOTICEdated 172015new.pdf

http://www.ipqpubs.com/wp-content/uploads/2015/10/CDSCO-MOU-FINAL-ENGLISH-Version.pdf

The Parenteral Drug Association Presents...

2015 PDA/FDAVaccines ConferenceThe New Vaccinology: Global Trends in Development, Manufacturing & Regulation

December 1-2, 2015 | Bethesda, MDBethesda North Marriott Hotel and Conference CenterExhibition: December 1-2 | Courses: December 3-4

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• Edward Patten, Associate Director, Manufacturing Science, CBER, FDA

• Rino Rappuoli, PhD, Chief Scientist, GlaxoSmithKline Vaccines

• David Wood, PhD, Coordinator, Quality Safety and Standards Team, Department of Immunization Vaccines and Biologicals, World Health Organization

• Kathryn Zoon, PhD, Chief, Cytokine Biology Section,Division of Intramural Research, NIAID, NIH

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SEPTEMBER 2015 �1 ......... ....


FDA Drug GMP Warning Letters and Recalls Posted in September

Warning Letters

Company Name Location Letter Date

Product Type

Areas Cited

International

Pan Drugs India 9/2/2015 API ● facility repair and maintenance ● equipment mainte-nance ● analytical testing

NOTE: At API manufacturer Pan Drugs in India, poor building and equipment maintenance that could lead to product contamina-tion and repeat observations from a previous inspection were in focus in the July 14-18, 2014 inspection. The letter notes that the firm ceased manufacturing operations two days before the FDA inspection began, and had also done so just prior to a 2011 inspection. On both occasions, Pan committed to complete various repair and renovation activities within 60 to 90 days, but had not done so since the 2011 inspection. FDA placed the firm on Import Alert in May 2015 until corrections were made and a successful follow-up inspection could takes place. FDA also recommended that due to ongoing GMP violations Pan should “en-gage a third party consultant with appropriate CGMP expertise to comprehensively assess your firm’s entire operation, including facility conditions, procedures, processes, laboratory controls, and quality management systems.”Jaychem Industries New Zealand 9/4/2015 Skin Care

Products● test method validation ● following SOPs ● OOS i●manufacturing SOPs ● lab testing ● stability ● mis-branding

NOTE: Jaychem is a contract manufacturer of skin care products, where the primary concern resulting from a July 7-10, 2014 inspection was a lack of assurance of the quality of components and active ingredients due to a lack of adequate SOPs. The letter also asserts that the firm failed to perform adequate testing, and released product regardless of the testing results. Its sunscreen products were deemed “misbranded” due to non-compliant labeling and directions for use.Unimark Remedies India 9/28/2015 API ● data integrity ● facility repair and maintenance

NOTE: The primary concern in the letter to API manufacturer Unimark resulting from a March 18-21, 2014 inspection is data integrity – specifically, batch records with signatures of operations personnel who were not on site when the operation was per-formed, laboratory systems that allowed all employees full access to all lab systems with no password protection and no audit trail, and failure to retain raw data. In the letter, FDA instructs the firm in its response to provide “a complete evaluation of the extent of inaccuracies in your reported data [and] a detailed action plan to investigate the extent of your deficient documentation practices.” Unimark was also cited for facility issues, including gaps in external walls that allow pests to enter, and bird feces and a live lizard observed in the raw material warehouse.

The following are the drug GMP warning letters posted by FDA during September, categorized into U.S. and International. The key concerns that each of the warning letters address and links to the letters themselves are provided. Included are notes on salient features of the warning letter with links to IPQ’s related cover-age.




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Recalls in September

JulyProduct Recaller # of

LotsClass Reason

Contamination / Lack of Sterility AssuranceVarious sterile compounded products

Liberty Drug and Surgical

48 II Lack of Assurance of Sterility: Process deficiencies were observed in the sterile ophthalmic and injectable products that could have compromised the sterility of the product.

Mupirocin ointment/cream

GlaxoSmith-Kline

22 II Penicillin Cross Contamination and Presence of Foreign Sub-stance. Product was contaminated with penicillin and foreign substances during manufacturing process.

Various compounded products

South Coast Specialty Compounding

>200 II Penicillin Cross Contamination: Multiple finished products po-tentially contaminated with penicillin.

Iodine surgical sol.

3M 4 II Chemical contamination: Product may be contaminated with a toxic compound.

Ropivacaine inj. Pharmedium One II Lack of Assurance of Sterility: The firm received a complaint of a sterility failure using a non-validated sterility test on a medica-tion cassette.

Ethyl alcohol surgical hand scrub

Healthpoint One II Chemical contamination; Naphthalene compound identified in the product after complaints of a petroleum odor.

Various sterile compounded products

Compounding Pharmacy of America

>1000 II Lack of Assurance of Sterility; FDA inspection identified GMP violations potentially impacting product quality and sterility.

Sodium chloride inj.

Baxter One II Lack of Assurance of Sterility: Recalling firm reported a com-plaint for mold on the interior surface of the overpouch.

Felodipine ER tabs; imipramine tabs

Mutual Pharma 23 III Chemical Contamination; benzophenone leached from the prod-uct label varnish.

Clomiphene tabs

EMD Serono One III Chemical Contamination: impurity failure due to chemical con-tamination of the active ingredient.

DissolutionLisinopril tabs Qualitest 2 II Failed Dissolution Specifications.

Dexmethylphe-nidate ER caps

Novartis One III Failed Dissolution Specifications: Product is being recalled due to out of specification (above specification) result obtained at 6-hour dissolution time point during the 12-month stability testing.

The following is a listing of the drug product recalls included in FDA’s weekly “Enforcement Reports” issued during September Included are the generic names of the products, the dosage form, the manufac-turer, the number of lots involved, FDA’s classification, and the specific reason provided by FDA in the Enforcement Report. The recalls are grouped by the general category of problem that caused them. The cat-egories are: ● compliance with NDA/monograph requirements ● contamination/lack of sterility assurance ● dissolution ● GMP/GDP ● impurity ● labeling/packaging ● foreign product ● particulate ● potency/content uniformity, and ● other spec nonconformance. Within the categories, the recalls are organized by class, with the most serious, Class I recalls at the top.

http://www.ipqpubs.com/wp-content/uploads/2015/09/Liberty-drug-recalls-Sept.-2015.pdf

http://www.accessdata.fda.gov/scripts/enforcement/enforce_rpt-Product-Tabs.cfm?action=select&recall_number=D-1362-2015&w=09022015&lang=eng

http://www.ipqpubs.com/wp-content/uploads/2015/09/South-Coast-Specialty-Compounding-September-2015-recalls.pdf




http://www.ipqpubs.com/wp-content/uploads/2015/09/Compounding-Pharmacy-of-America-September-2015-recalls.pdf







SEPTEMBER 2015 �� ......... ....


ImpurityPhentermine caps

KVK-Tech 2 III Failed Impurities/Degradation Specifications: out-of-specifica-tion results for individual unknown and total impurity at the 12th month room temperature stability test station.

Desoximetasone topical spray

Taro 2 III Failed Impurities/Degradation Specifications: Out of specifica-tion results for impurities testing was obtained at the 6 and 9 month time points.

Labeling / PackagingOTC cold medi-cation

Reckitt Benckiser

>100 I Labeling: Label Mix-Up; Bottles of Mucinex Fast-Max liquid are correctly labeled on the front of the label, however the back of the bottle where the Drug Facts labeling is, is missing certain Active Ingredients such as acetaminophen, phenylephrine, dextromethorphan, diphenhydramine, and/or guaifenesin. As a result certain safety warnings associated with those ingredients may also be missing.

Ketamine inj. Hospira 2 II Defective Container: There were customer complaints of cracked and leaking glass vials.

Lamivudine oral sol.

Silarx One III Labeling: Incorrect or Missing Lot and/or Exp. Date - Firm re-ceived a customer complaint that the expiration date printed on the unit carton (5/18) does not match the expiration date on the bottle label (5/17).

Foreign Product

Hydrochloro-thiazide tabs

Unichem One II Presence of Foreign Tablet: A pharmacist found a clopidogrel tablet in the 1000-count bottle of hydrochlorothiazide 25 mg tablets.

Cough drops Bestco 3 III Presence of Foreign Tablets/Capsules: Presence of comingled Sugar Free Honey Lemon cough drops.

Particulate

Fluorouracil inj. Teva 6 I Presence of Particulate Matter: Silicone rubber and fluorouracil crystals found floating in solution.

Various compounded sterile products

Pharmedium Services

I Presence of Particulate Matter: The firm produced products using 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP which were subsequently recalled by the manu-facturer due to the presence of particulate matter.

Ophthalmic ointment

Allergan Sales 50 II Presence of Particulate Matter: Due to customer complaints of small black particles, identified as part of the ointment tube cap, generated by the action of unscrewing the cap from the aluminum tube and potentially introducing the particle into the product.

Lidocaine inj. Hospira One II Presence of Particulate Matter: particulate matter identified as iron oxide, was found embedded in the neck of glass vials.

Potency / Content Uniformity

Amlodipine/ atorvastatin tabs

Dr. Reddy’s 11 III Subpotent Drug: Subpotent atorvastatin.

Indocyanine green inj.

Akorn One III Subpotent Drug: Low out-of-specification potency result of the drug product.

Other Spec NonconformanceCevimeline caps Apotex 10 II Failed Stability Specifications: product may not meet specifica-

tion limit for assay test.

27









http://www.ipqpubs.com/wp-content/uploads/2015/09/Pharmedium-Services-September-2015-recalls.pdf








Allopurinol tabs Qualitest One III Failed Tablet/Capsule Specifications; report of oversized and discolored tablets.

Methocarbamol tabs.

Golden State Medical Supply

One III Failed pH specification.

Ophthalmiclubricant drops

Oasis Medical One III Failed stability specifications: This recall has been initiated due to out of specification results for viscosity.

General Information

Program Description

Register by November 9 and SAVE!

Attend To:

● Explore the trends behind increased enforcement actionsGet tips and best practices for responding to enforcement action by FDA or another agency

● Learn how to comply with new and upcoming FDA rules and regulations

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● Address specific issues in food, drugs, biologics, medical devices, andtobacco.

Keynote Speakers:

Jonathan Olin, Deputy Assistant Attorney General, Civil Division, Department of Justice

George Karavetsos, Director, Office of Criminal Investigations, Food and Drug Administration

Who Should Attend:

Attorneys Regulators Compliance specialists Consultants Litigators Regulatory Personnel Academics

Audience:

Food Drugs, Medical Devices, Animal Drugs Biologics Diagnostics Dietary Supplements Tobacco




Jerry

Rectangle

http://www.fdli.org/enforcement2015/general-information

http://www.fdli.org/enforcement2015/agenda

INTERNATIONAL PHARMACEUTICAL QUALITY

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