gmp/inspection - international pharmaceutical … task force leader steve mendivil (amgen) ... cylia...

MONTHLY UPDATE - JULY/AUGUST 2015

GMP/INSPECTION

• Culture and Process Capability Continue in Focus as FDA Releases Its Draft Quality Metrics Guidance......................3

• Wave 2 of ISPE’s Quality Metrics Pilot Will Explore Metric Relationships and How to Deepen Industry’s Role inAdvancing the Regulatory Process....................................................................................................................................................11

UNITED STATES

UPDATES IN BRIEF - p. 43

U.S CMC: • Dissolution Guidance • Analytical Methods Guidance • Injectable Drug Excess Guidance • PDUFA Hearing • GDUFA Approval • Outsourcing Guidance • Rare Disease Drug Development • Botanicals GuidanceU.S GMP: • Drug Shortage Notifications •Product Tracing Compliance Guide • Legionaire’s Bacteria at GSK •USP/USAID Secure Supply Chain

EUROPE CMC: • IMP Consultation • Fast-Track Guidelines • ATMP Recommendations • Electronic Applications • EU/Swiss Confidentiality Agreement • PhEur on Elemental Impurities EUROPE GMP: • FMD Safety Features Draft • Parallel Distribution Database • Brazil & Israel on Approved API List • Tissue Establishment Inspections • GMP/GDP Non-Compliance • MHRA on Data Integrity • MHRA License Suspensions

INTERNATIONAL CMC: • ICH M7 Addendum • Nano-Crystal Medicines • TGA EU Guideline Adoption • CFDA Approval Process • CFDA Application Self-Audits • Shanghai CenterINTERNATIONAL GMP: • PIC/S Annex 15 • WHO Biologics Guide • ASTM Continuous Processing Guide • TGA EU Guide-line Adoption • India Bar Coding • India Material Sampling • CFDA Surprise Inspections

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INTERNATIONAL PHARMACEUTICAL QUALITYInside the Global Regulatory Dialogue

VOL. 7, NO. 4

FDA WARNING LETTERS AND RECALLS POSTED IN JULY AND AUGUST - p. 54

INTERNATIONAL

CMC/REVIEW

• Relationship with Excipient Providers Drawing Increasing Pharma Attention, BMS Exec Stresses; IPEC UrgesRegulatory Pathway for New Excipients in GDUFA/PDUFA Comments..................................................................................28

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INSIDE THE GLOBAL REGULATORY DIALOGUE™

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UNITED STATESCulture and Process Capability Continue In Focus as FDA Releases Its Draft Quality Metrics GuidanceFDA is asking for industry input on how quality culture and process capability evaluations can contribute to the “baseline” metrics it has put on the table for review in its draft quality metrics guidance.

Released in late July, the draft guidance and the accompa-nying Federal Register announcement point to the impor-tance of quality culture and process capability in advancing drug quality and its regulation and invite industry to join with the agency in probing further into the role the two issues can play in conjunction with its metrics initiative. [Links to the draft guidance and Federal Register notice are provided below.]

The guidance and announcement provide a detailed explanation of the development of the metrics initiative and its purpose in helping the agency refine its risk-based compliance and inspection policies, reduce drug shortages, and encourage better quality management systems and manufacturing innovation.

The agency points out that culture and performance have been prominent themes in the metrics dialogue and will continue to be so as the iteration process with industry continues.

The draft guidance stresses the importance of quality culture to “the overall state of quality of the product, process and commitment to quality.”

Similarly recognized is the importance of statistical analysis in understanding and managing product and process variability, enabling post-launch learning and advancing product quality.

Along with ten specific data points to be provided by industry and four performance metrics that FDA will calculate from them, the guidance proposes three additional “optional” metrics that could be submitted “as evidence of manufacturing robustness and a commitment to quality.” Two of these relate to an organization’s quality culture and the third to its process capability program.

The agency asks for feedback from industry on whether the three metrics are fit for purpose and invites comment on optional metrics that should be considered.

PDA and ISPE Initiatives Shed Light on Assessing Culture

Reflective of the emphasis that quality culture has been getting from FDA in the context of its metrics initiative, both PDA and ISPE established task teams to examine how culture can be meaningfully assessed and improved.

Both teams have arrived at the general conclusion that quality culture is a complex and nuanced issue for organizations and caution against over-simplifying the elements involved.

The work the two association teams have been doing will provide a foundation for further agency/industry dialogue on how the regulatory process and quality culture can meaningfully intersect and foster advancement.

At the PDA annual meeting in April, PDA Quality Metric Task Force Leader Steve Mendivil (Amgen) updated the audience on the work of his group.

Mendivil stressed the communication and alignment of

Optional Metrics Related to Quality Culture and Process Capability

The following are the three “optional” metrics FDA is proposing for industry comment related to quality cul-ture and process capability.

• Senior Management Engagement:Was each APR or PQR reviewed and approved by the fol-lowing: (1) The head of the quality unit, (2) the head of the operations unit, (3) both, or (4) neither?

• Corrective Action and Preventive Action (CAPA) Effectiveness:What percentage of your corrective actions involved re-training of personnel (i.e., root cause of the deviation is lack of adequate training)?

• Process Capability/Performance:1) A “yes” or “no” value of whether the establishment’s management calculated a process capability or perfor-mance index for each critical quality attribute as part of that product’s APR or PQR.

2) A “yes” or “no” value of whether the establishment’s management has a policy of requiring a CAPA at some lower process capability or performance index.

3) If “yes” to the previous question – what is the process capability or performance index that triggers a CAPA? If “no” to the previous question – please do not respond.


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efforts that has been taking place between the major trade associations to rationalize industry’s available resources. With ISPE focused on its quality metrics pilot, he explained, PDA decided it could best serve the overall cause by concentrating, in particular, on the cultural component.

Building on the task force’s analysis, which was informed by the trade association submissions and the metrics forums held by PDA in late 2013 and the Brookings Institute in April 2014, PDA issued a quality culture survey to their membership in September 2014 designed to explore the relationship between the maturity of quality attributes and evidence of positive quality culture behaviours at a firm.

The survey participants were questioned about their views on key mature quality attributes and areas of positive quality culture behaviours that the task force had delineated (see box below).

In December 2014, PDA held a conference focused specifically on quality culture at which the survey results were discussed and the five quality attributes deemed most significant were brought forward. Five areas of further interest were added to the list through discussion of the experience of the participants and consensus voting (see box below).

PDA will be holding another quality metrics/culture conference in November 2015 co-sponsored by FDA. The conference will include a focus on how the maturity and robustness of a company’s program could actually be assessed during an inspection or audit based on these nominated quality attributes.

In offering some “final thoughts” at the PDA annual meeting breakfast session, team leader Mendivil pointed out that “it is clear that there are no perfect quality metrics.” The goal is to understand the trade-offs – what the unintended consequences may be and how to circumvent them – “because if you don’t, you are getting data that you can’t rely on.”

In considering quality culture/mature quality attribute metrics, he pointed out, you are outside the established GMP framework. Noting that FDASIA refers to collecting GMP information, he suggested that expanding the framework is an issue that needs to be “grappled with” as the industry/FDA work in this arena continues.

Pointing to the presentations given at the December 2014 conference by quality heads of big and small companies, Mendivil commented that “it was clear that many companies are embracing

PDA Quality Metrics Task Force MembershipThe following are the members of PDA’s Quality Metrics Task Force in April 2015:

Chair: Steve Mendivil, Amgen Joyce Bloomfield, MerckCylia Chen-Ooi, AmgenVeronique Davoust, PfizerGabriele Gori, GSK VaccinesRobert Kieffer, ConsultantEdwin Rivera Martinez, SanofiMarty Nealey, HospiraPritesh Patel, AllerganAnil Sawant, J&JSue Schniepp, ConsultantAnders Vinther,Sanofi PasteurGlenn Wright, Lilly

PDA Staff: Denyse Baker, Morgan Holland, Rich Levy

Quality Attributes and Culture Behaviors Surveyed PDA

PDA’s task force delineated the following seven key mature quality attributes and quality culture beha-viours as the foundation for its 2014 survey. Mature Quality Attributes• Prevention Programs• Quality Management and Issue Escalation• Training and Personnel Development• Quality System Management• People and Communication• Continuous Improvement• Site Metric Reporting

Quality Culture Behaviors• Communication and Transparency• Commitment and Engagement• Technical Excellence• Standardization of Criteria or Requirements• Cross Functional Vision• Rewards and Recognition• Speak Up for Quality Culture

PDA’s Ten Key Mature Quality AttributesTop 5 Mature Quality Attributes arising from PDA Survey• Management communication “Quality is Everyone’s re-sponsibility”• Formal site quality improvement objectives and targets• Clear performance critera for feedback and coaching staff• Quality topics are included in at least half of All Hands meetings• Collecting error prevention metrics

Top 5 Mature Quality Attributes arising from Confer-ence Participants• Program of every employee understands quality goals and how their specific goals contribute• Program to measure, share and discuss product quality performance and improvement from shop floor to executive management• Program with active support of CEO and Corp Manage-ment of QMS and continuous improvement plans• Program that establishes quality system maturity model and action plan and tracking to measure progress• Internal survey measuring a company/site quality culture


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quality culture…and making tremendous efforts to strengthen their quality culture. They see it as a critical aspect to maintaining product quality.”

In an article previewing the upcoming conference in the July/August PDA Letter, conference co-chairs Mendivil and CDER’s Russ Wesdyk emphasize that “regardless of what metrics need to be submitted to FDA, a company should create and use metrics within their organization that make a difference and add unique value to its products and culture.”

The conference, in turn, will delve into “how to establish and build an efficient and effective quality metrics program with limited resources and how such a program can drive not only product quality improvements but also foster a strong quality culture.”

ISPE Introduces Cultural Excellence Framework

While the ISPE metrics effort has been primarily focused on their industry pilot (see story on pp. 11-27), the association also set up two working groups to explore the themes of quality culture and process capability.

The ISPE quality culture sub-team has developed a “six dimensions of cultural excellence” framework as part of its effort to offer practical tools, templates and training to the industry on advancing the development of healthy quality cultures.

At the ISPE “Quality Metrics Summit” in Baltimore in April, ISPE Quality Culture Team lead Nuala Calnan from the Dublin Institute of Technology, updated the audience on the team’s work and its development of the cultural excellence framework.

She explained that each organization will have a different context within which their quality culture exists based on organizational ownership, supply chain configuration, maturity, product mix and regional influences.

The ISPE team proposes that the promotion of a “relentless restlessness” towards improvement in quality culture necessitates a 360° approach to cultural excellence, and cautions against believing that there is a “silver bullet” solution to assessing or measuring culture.

The six dimensions framework commences with leaders establishing and engendering the vision for quality, which fosters and develops employee attitudes and mindsets. Assessing the actual behaviors on the shop floor is then facilitated through the use of Gemba walks and other coaching mechanisms.

A key element of the process involves the proactive monitoring and surveillance of key triggers and leading indicators of quality. The leaders must then subject the results and outcomes to appropriate and timely oversight and review.

The final dimension outlines the crucial “cultural enablers” such as the development of a learning organization, influencing and recognizing organizational change and proactive problem-solving techniques.

The ISPE sub-team will continue working to bring forward practical implementation tools for firms to build internal capabilities in these areas, Calnan said.

Culture Foundational to a Quality System

CDER Director Janet Woodcock reaffirmed her focus on the role culture plays in the quality arena in her keynote at the ISPE April metrics summit, which she framed with the provocative title “The Quality Revolution: The Future of Pharmaceutical Manufacturing and its Regulation.” [For an in-depth review of Woodcock’s presentation and the discussion that followed, see IPQ “Monthly Update” April/May 2015, pp. 3-13.]

Woodcock posited that the way FDA has traditionally approached industry and communicated its expectations helped produce a culture of compliance and relationship of fear with the industry – a relationship that does not “grow a quality culture” and one the agency is now trying to change.

Acknowledging that quality culture is some-thing that is “very hard to measure,” Woodcock emphasized that a quality system is only as good as the culture that supports it.

Principles of ISPE’s “Six Dimensions of Cultural Excellence

1) Leaders establishing and engendering the vision

2) Development of the employee & mindsets

3) Assessing the behaviors through Gemba walks

4) Monitoring & surveillance of the key triggers & lead-ing indicators of quality

5) Oversight, reporting & reviews by leaders

6) Building competencies for cultural enablers such as: • learning organization development • development of learning teams influencing & recognizing change • proac-tive problem-solving, and • getting to the true root cause

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





In her remarks on the release of the draft guidance, provided in an accompanying CDER webinar in late July, Woodcock again reiterated the importance of quality culture as an indicator of the maturity of an organization’s quality management program and of senior management’s engagement.

Along with promoting responsible practices and a quality-driven corporate culture, other goals central to the metrics effort, she stressed, are: ● identifying situations in which there may be a risk of drug supply disruption ● improving FDA’s evaluation of drug manufacturing and control operations ● improving the efficiency and effectiveness of establishment inspections, and ● further developing the agency’s risk-based inspection scheduling.

FDA Holds Forum in Late August to Expand Industry Input

In addition to the list of proposed metrics, the draft guidance provides details in separate sections on: ● the legal authorities FDA has for metrics data collection through its process validation and FDASIA rules ● how FDA intends to use the data and the effects of non-reporting, and ● the expectations for who needs to be involved in the reporting process, what data needs to be reported (see box at right), and how.

Included are a glossary of the key terms involved and an appendix with more detailed instructions on the reporting requirements.

Data/Metrics Called for in FDA’s Draft Guidance

Data Points to be Reported to FDA by Industry

1) The number of lots attempted of the product.2) The number of specification-related rejected lots of the product, rejected during or after manufacturing.3) The number of attempted lots pending disposition for more than 30 days.4) The number of OOS results for the product, including stability testing 5) The number of lot release and stability tests con-ducted for the product6) The number of OOS results for lot release and stabil-ity tests for the product which are invalidated due to lab error.7) The number of product quality complaints received for the product8) The number of lots attempted which are released for distribution or for the next stage of manufacturing the product9) If the associated APRs or PQRs were completed within 30 days of annual due date for the product10) The number of APRs or PQRs required for the prod-uct

Metrics to be Calculated by FDA

1) Lot acceptance rate2) Product Quality Complaint Rate3) Invalidated Out-of-Specification (OOS)4) Annual Product Review (APR) or Product Quality Review (PQR) on Time Rate


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FDA explains that its criteria in choosing metrics are: ● objectivity ● ability to be inspected in conformance with the stipulations in section 704 of FDASIA ● value in assessing the overall state of quality of a product, and ● not requiring an undue reporting burden.

While how the metric choices match up with these criteria have been and will continue to be discussed, the reporting burden aspect is likely to draw particular attention in industry’s feedback on the draft.

In addition to opening up the draft for written comment, FDA is holding a public meeting on August 24 to provide another pathway “to gain stakeholders’ perspectives on various aspects of the development and planned implementation” of the quality metrics program, including the initial set of data requests.

ISPE, PDA, PhRMA, the Consumer Health Products Association (CHPA), the Generic Pharmaceuticals Association (GPhA) and the International Pharmaceutical Excipient Council (IPEC) are among the organizations that are on the agenda for the meeting. FDA’s CDER will be represented by Woodcock and senior representatives from several of the OPQ offices involved.

Iterative Metrics Process Will Involve Industry

FDA stresses in the draft guidance and accompanying Federal Register notice (FRN) that the metrics will be used in considering how to decrease inspection surveillance and post-approval change filing burdens where they support doing so.

Further highlighted is the role that industry has played and will be expected to play in shaping and refining FDA’s overall proposed metrics approach so that its objectives are achieved.

The agency is notably transparent on where the uncertainties and gaps lie to date and further industry input is especially important and sought.

FDA also makes clear that the process of determining how the metrics should be collected, interpreted and used will continue to be an iterative one, and that industry will be provided with ongoing opportunities for feedback and comment to help assure that the initiative has the intended progressive impact on the quality regulatory process.

The metrics draft guidance is unusual in that it focuses as much on highlighting and clarifying the issues that need further consideration, dialogue and resolution as it does giving directions on current expectations and procedures.

The draft indicates that FDA will be evaluating how

best to interpret and use the metrics it receives, and “may add to, revise, or remove quality metrics data from future requests to reflect our understanding of current manufacturing and establishment considerations and the utility of the data the agency has received.”

In turn, it stresses, industry will have additional opportunity after the initial requests are made “to provide feedback and additional comments, as well as share knowledge from ongoing quality metrics programs.”

Among the live questions on the table, the draft explains, are:

● “Is it more meaningful to compare metrics for different products within the same establishment, or for the same product manufactured at different establishments, or as an establishment-specific trend over time?”

● “Is it more appropriate to use certain metrics to compare all types of establishments (or a subset making the same dosage form or same drug) against each other?”

● “What is the best way to compare metrics for products that vary in manufacturing complexity (e.g., biotechnology and biological products are often considered more complex to manufacture)?”

The accompanying FRN highlights nine questions on which the agency is seeking input from stakeholders, in particular (see box on p. 8).

These range from whether the metrics definitions provided are adequate, through examining the relevance of particular measures to different industry sectors, to considerations of applying metrics to high-risk excipient suppliers.

The potential to include a “right first time” measure, and how that measure might be designed, is singled out for specific input. Opinions are also sought regarding frequency of reporting either annually, semi-annually or quarterly.

Two questions in particular address the potential hurdles in the reporting process and seek suggestions on “alternative approaches” to reduce the burden of reporting.

The first question requests if there are data standards that should be considered to aid or simplify the submission process. Reflective of the outstanding questions noted in the guidance, the second question examines the challenges of collecting metrics either at a product level (segmented by site) versus collecting them at a site level (segmented by product).




Suggested alternative approaches to reduce burden are likely to be an area of keen focus in the responses from industry.

Product Level Reporting Burden Will Draw Comment

The responses from industry in relation to reporting burden are likely to focus on FDA’s intention to ask industry to submit metrics at a product level.

The draft calls for one report for each finished dosage form (FDF) and one report for each active pharmaceutical ingredient (API) used in its manufacture to be filed for products covered by the guidance.

Quality metrics data from each establishment involved in the manufacture will need to be collated across the supply chain. The guidance notes that the “reporting establishment” should combine the data so that a single report is submitted for each FDF and each API.

The numbers of reports this entails are not small. FDA

estimates that it will receive 63,000 product level reports from across the new drug, generic and OTC sectors. 25,000 are expected for drugs subjected to approved marketing applications or covered by a drug master file and 38,000 for drugs not subject to approved applications (those marketed pursuant to an OTC monograph and marketed unapproved drugs).

Industry has voiced concern about this large volume of data that will need to be collected, collated and reported by industry and reviewed by FDA.

Although the majority of facilities currently have their own metrics programs in place, responsibility for these programs largely reside and are managed at a site level, with a more limited number of measures being periodically reported centrally to corporate HQ. In turn, reporting of product metrics across the entire supply chain may be difficult for many firms, at least in the early stages of the FDA implementation process.

Although the majority of facilities currently have their own metrics programs in place, responsibility for these programs largely reside and are managed at a site level, with a more

QUESTIONS FROM FDA FOR STAKEHOLDER INPUT

The following are nine questions FDA is asking industry for input on, in particular, in commenting on the draft guidance and its metrics:

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

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

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

4) 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?

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

6) Should the Agency add “Right First Time” metris (see section 1), and if so, should the definition be a rework/reprocessing rate or a measure of lots manufactured without processing deviations?

7) What data standards/mechanisms would be useful to aid reporting and how should the submissions be structured?

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

9) 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)?


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Evolution of the Recommended Metrics – Brookings v. ISPE v. FDA

The following is a comparison of the “consensus” metrics proposed by the Brookings Institute in April 2014 based on the industry/agency dialogue at its meeting, the metrics recommended by ISPE in April 2015 from its Wave 1 pilot, and those in the FDA draft guidance issued in July 2015. When considered side-by-side, the evolution in the individual metric definitions can be seen to have been informed by the ongoing agency/industry dialog over the past two years. All three organizations include a version of both lot acceptance rate and product complaint rate. Brookings and FDA have an out-of-specification measure, albeit with significantly different definitions and scope. ISPE’s Wave 1 findings did not support a significant correlation with an OOS metric, and although it was studied in the Wave 1 pilot, the association did not include it in their ‘starter set’ recommendations list. All three have a unique additional measure they recommend. For Brookings this was recall rate, for ISPE, deviations rate, and in the FDA draft guidance metrics we see a measure related to the annual product review (APR) or product quality review (PQR) on time rate.


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limited number of measures being periodically reported centrally to corporate HQ. In turn, reporting of product metrics across the entire supply chain may be difficult for many firms, at least in the early stages of the FDA implementation process.

Driving the Global Dialogue

In considering how to use metrics to advance FDA’s quality regulatory process, both industry and agency representatives have been expressing concern about the global environment in which the initiative is taking place and the importance of driving international convergence to achieve the intended results.

In her presentation at the April ISPE metrics summit, CDER’s Woodcock stressed that globalization is bringing urgency to the pharmaceutical industry’s quality culture advancement and to the regulators’ search for more effective and harmonized regulatory processes that can support it.

As FDA’s management of pharmaceutical quality regulation becomes more standardized and more formalized, “then how do we engage with all the other inspectorates, both in the developed world and all of these emerging inspectorates?” she queried. “How do we get to a better place where quality is not equated with having 20 inspectors visit a facility every year? I recognize that is a real big problem. That is a problem for quality, in general, if you are going to focus all of your attention on that.”

Providing an update on the PDA metrics effort at the ISPE annual meeting in November 2014, Mendivil advocated the search for “globally applicable” metrics.

“One of the things that we are trying to get our arms around is, is there more of a global perspective on this so we are not having to generate a different set of quality metrics for 170 different regulatory agencies? That would be a little

burdensome,” the PDA task force leader wryly pointed out.

Mendivil highlighted the concern with global metrics again in his update at the PDA annual meeting in April. Europeans are generally taking the approach that metrics would be assessed as part of inspections rather than being submitted to the agency – something the PDA task force believes “is really a good approach.”

In reviewing the ISPE metrics effort at the ISPE metrics summit and at the June ISPE conference,Genentech Global Quality Systems and Processes VP Diane Hagerty, who co-leads the ISPE metrics project team, also stressed the importance that her team is placing on maintaining an international perspective and enabling a data-driven dialogue with other health authorities (see story on pp. 11-27).

She pointed out that the European health authorities are actively collecting information to inform their risk-based inspection schedules and are watching with interest and engaged in the metrics dialogue. “They are indicating they are not really looking at moving forward right now with a metrics submission program.” However, Hagerty stressed, “we want to make sure we are maintaining that dialogue worldwide” and using the industry learnings to help shape it.

She underscored the value of FDA’s metrics initiative in enabling “the ongoing objective and data-driven dialogue” not only with FDA but with other health authorities as well – a “piece of this that is really important to keep in mind.”

DOWNLOADS FROM THE STORY:

• FDA Quality Metrics Draft Guidance • Federal Register Notice

http://www.ipqpubs.com/wp-content/uploads/2015/08/Guidance-Req-for-QUality-Metrics-27July2015.pdf

http://www.ipqpubs.com/wp-content/uploads/2015/08/Federal-Register-_-Request-for-Quality-Metrics-Notice-of-Draft-Guidance-Availability-and-Public-Meeting-Request-for-Comments.pdf

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Wave 2 of ISPE’s Quality Metrics Pilot Will Explore Metric Relationships and How to Deepen Industry’s Role in Advancing the Regulatory ProcessWave 2 of ISPE’s quality metrics pilot is being designed to enhance the understanding of the relationships between the metrics that emerged into relief during Wave 1 and to provide further support for FDA in developing a more data-driven regulatory process.

To help enrich the data set and its value, ISPE is seeking to: ● increase the number of sites, technologies, company typesand geographies that are involved in the Wave 2 effort ● collect data over a longer time to examine trending patterns, and ● evaluate the logistics of gathering product data at an application level.

The larger Wave 2 goal, ISPE is stressing, is to deepen the dialogue on how to achieve the 21st Century vision enunciated by CDER Director Janet Woodcock of a more flexible, efficient and transparent regulatory process and to move industry into a more prominent role in achieving it.

The release by FDA in late July of its quality metrics draft guidance as the ISPE Wave 2 effort is getting underway (see story on pp. 3-10) was anticipated, and allowance has been made in ISPE’s planning process for the draft guide’s influence.

Although ISPE did not have the advantage of having the FDA draft guideline in hand during either its Wave 1 effort or in planning for Wave 2, the insights the association has garnered do resonate with the agency draft. Similarly, while FDA did not have the ISPE report available when it was formulating its draft, the influence of the open exchange of views between the agency and industry over the drafting period is clear.

The draft guidance and the Federal Register announcement accompanying its release provide a detailed explanation of the development of FDA’s quality metrics initiative and its purpose of helping the agency refine its risk-based compliance and inspection policies, reduce drug shortages, and encourage better quality management systems and manufacturing innovation.

The draft and the announcement highlight the role industry has played and will be expected to play in shaping and refining FDA’s proposed metrics approach. [Links to the draft guidance and Federal Register notice are provided below.]

The agency is transparent on where the uncertainties and gaps lie to date and further industry input is especially important and sought.

FDA also makes clear that the process of determining how

the metrics should be collected, interpreted and used will continue to be an iterative one, and that industry will be provided with ongoing opportunities for feedback and comment to help assure that the initiative has the intended progressive impact on the quality regulatory process.

In addition to opening up the draft guidance for submitted comments, FDA will be holding a public meeting at its White Oak headquarters on August 24 as another pathway “to gain stakeholders’ perspectives on various aspects of the development and planned implementation” of the quality metrics program.

ISPE is preparing its response to FDA on the new guidance in two phases: The association is requesting a speakers slot at the August 24 meeting and will be submitting comments on the draft guidance. PDA has also indicated that they will be collating member comments on the draft guidance to

provide input to FDA.

ISPE Wave 1 Explored Metrics Reporting Challenges

ISPE initiated its quality metrics initiative in mid-2013 in response to an FDA Federal Register notice (FRN) earlier that year in which FDA asked for industry support in establishing a metrics collection approach that would be fit for purpose (see IPQ “Monthly Update” June 2013, pp. 12-20).

The 2013 announcement explained that, as part of its drug shortage prevention effort, the agency was exploring how the collection of quality metrics would further its goals of understanding the state of quality across industry and creating a more strategic, risk-based regulatory process that would focus on the manufacturing vulnerabilities and foster preventative quality system improvements.

The announcement elicited a broad response from across the industry. By late 2013, in response to a follow-up request from FDA for input on specific metrics that would be viable, substantive submissions had come in from ISPE, PDA, the Pharmaceutical Research and Manufacturers of America (PhRMA), the Generic Pharmaceutical Association (GPhA), and the Consumer Healthcare Products Association (CHPA).

In the wake of FDA’s request for industry help, ISPE published a quality metrics white paper in December 2013. The paper recommended that a pilot

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program be conducted to further understand the implementation opportunities and the challenges involved in measuring and centrally reporting performance metrics.

Further industry/agency dialogue was facilitated at a key meeting held at the Brookings Institute in April 2014 leading to the publication of a proposed set of four “consensus” metrics: ● lot acceptance rate ● product complaint rate ● confirmed out of specification rate, and ● recall rate.

Following through on the recommendation in its December 2013 paper, ISPE commenced a six-month “Wave 1” quality metrics pilot in June 2014. The pilot included the collection and analysis of quality metrics at forty-four sites from eighteen different companies in the effort to flesh out viable definitions and approaches.

Wave 1 Results Reported at April �01� Summit

The results from the wave 1 pilot were presented and discussed at an ISPE “Quality Metrics Summit” held in Baltimore in April 2015 (see IPQ “Monthly Update” April/May 2015, pp. 25-34) and have been consolidated into a final report, which was released by ISPE’s metrics team in June.

The opening session of the April summit included presentations from Office of Pharmaceutical Quality (OPQ) Office of Policy and Product Quality (OPPQ) Acting Director Ashley Boam, who explained the relationship of the metrics initiative to the FDA Safety and Innovation Act (FDASIA) and OPQ’s mission, and Merck Exec. VP and Manufacturing Division President Willie Deese, who provided an industry perspective on the importance of quality metrics to manufacturing performance and explained Merck’s metrics program.

In line with a presentation she had given at the University of Georgia/FDA GMP conference a month earlier (ibid.), Boam explained how the metrics collection effort would, on the one hand, help FDA predict quality problems and work with firms to resolve them ahead of manufacturing breakdowns and drug shortages, and on the other, provide leverage for greater regulatory flexibility commensurate with the state of a manufacturer’s pharmaceutical quality system and demonstrated product/process knowledge – a goal central to its “21st Century” effort and OPQ’s mission.

Outlining the tiered approach to metrics that is currently deployed throughout Merck’s manufacturing network, Deese stressed that the measures and metrics selected must reinforce the connection between the shop floor and the overall business goal of a safe, compliant, and reliable supply.

This can only be achieved by driving a culture of accountability, transparency and continuous improvement across the organization, the Merck exec maintained. Leadership is critical to enabling the right culture, he emphasized, and requires consistency of purpose in order to ensure that everyone in the supply chain is focused on the patient.

Deese was followed at the podium by Genentech Global Quality Systems and Processes VP Diane Hagerty, the leader of the ISPE Quality Metrics Project Team, who summarized the key learnings gained from the Wave 1 pilot. She described the pilot’s: ● background and context ● design and operation ● data analysis methods and outcomes, and ● next steps. [Hagerty’s complete remarks are provided below.]

The ISPE pilot program was executed in partnership with the management consulting firm McKinsey. Hagerty was accompanied at the session by McKinsey Partner Paul Rutten and Senior Knowledge Expert Vanya Telpis, who provided more detail on the data collection, analysis and results.

The conclusion from the pilot experience, Hagerty summarized, was that it is feasible to collect a standardized set of metrics across companies. However, the report stresses that it is important to start with a targeted set of “relatively well established” metrics at both the site and product level in order to build measurement, reporting and analysis capabilities across both industry and FDA.

The report also highlights the level of effort involved at an individual site level to collect and externally report a set of standardized metrics. It notes that although the majority of sites are currently collecting metrics internally, the additional burden associated with a centralized reporting system to the agency should not be underestimated.

In light of the fact that FDA has now indicated its intention to ask industry to submit metrics at a product level collated across the supply chain, the issue of how the proposed metrics will be reported to FDA will continue to be a key one for discussion between the agency and industry (see story on pp. 3-10).

CDER’s Woodcock Addresses “The Quality Revolution”

The April summit was structured to elicit the experiences and views of the attendees and help build the foundation for the Wave 2 effort.

Case studies were presented by Procter & Gamble Site Quality Program Manager Kristi Castro and Sandoz Quality Executive Director Lauri Hubbard on their companies’




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data collection, submission and benchmarking experiences as Wave 1 pilot participants and how the pilot drew on their existing metrics programs and expanded their reach. Breakout groups were then held to explore the pilot experiences and learnings further with the other meeting participants.

The keynote presentation on the second day of the summit was given by CDER Director Janet Woodcock, which she framed with the provocative title “The Quality Revolution: The Future of Pharmaceutical Manufacturing and its Regulation.” [For an in-depth review of Woodcock’s presentation and the discussion that followed, see IPQ Monthly Update April/May, 2015, pp. 3-13.]

Woodcock addressed the concern industry has expressed around the potential for a quality metrics submission program to create fear and encourage behaviors contrary to CDER’s stated objectives of improving quality management systems and encouraging continuous improvement.

Responding directly to that concern in her presentation, she affirmed the Deming principle that fear-based relationships – both internally within companies, and between themand the agency – are indeed antithetical to quality system advancement, and that the principle is fundamental as the agency reshapes its regulatory approach. In turn, while fear is a roadblock on the continuous improvement pathway, measurement is a critical driver, Woodcock said, in explaining the principles underpinning FDA’s “quality revolution.”

[Editor’s Note: See IPQ Monthly Update April/May, 2015, pp. 3-13 for an analysis of the relevance of Deming’s quality philosophy to pharma manufacturing via the insights provided by Deming Institute expert at a PDA/FDA workshop on quality systems. Pharma is tapping into only a relatively small part of its power, he said, explaining what the industry needs to do to take hold of the rest.]

How Does Quality Culture Tie In?

Quality culture and its relationship to metrics received attention at various junctures during the two-day ISPE metrics summit.

The first day concluded with a presentation by Perrigo Global Quality Exec VP Louis Yu, in which he addressed the importance of quality culture to business success in the pharmaceutical industry and shared Perrigo’s experiences in developing a healthy organizational culture.

Following Woodcock on the second day was ISPE’s Quality Culture Team lead Nuala Calnan from the Dublin Institute of Technology, who described the

“six dimensions of cultural excellence” framework her team has developed as part of its effort to offer practical tools, templates and training to the industry on advancing quality culture (see story on pp. 3-10).

Breakout groups were then held to discuss: ● the role quality culture plays in tackling persistent data integrity issues ● if the influence of quality culture can be measured in an organization, and ● what quality culture “looks and feels like,” and how Gemba walks can be used as a means to both foster and monitor progress.

The April summit concluded with breakout group readouts, brief summary remarks by ISPE President John Bournas and Genentech/Roche Pharma Technical Quality Global Compliance and External Collaboration VP and summit co-chair Joe Famulare, and a panel discussion of how the Wave 1 pilot learnings can inform the Wave 2 effort.

The panel included OPQ’s Boam and its Office of Sur-veillance Acting Director Russ Wesdyk, who has played a lead role in FDA’s metrics initiative (see IPQ “Monthly Update” June 2013, pp. 12-. Offering a Center for Biologics (CBER) perspective on the panel was its Office of Compliance and Biologics Quality Director Mary Malarkey.

Wave 1 Report Released, Wave � Discussed at June Conference

ISPE’s quality metrics dialogue continued at its June “quality manufacturing” conference, which was co-sponsored by the Product Quality Research Institute (PQRI) and FDA. The official release of the Wave 1 report coincided with the conference.

The comprehensive 102 page report covers the background and design of the pilot, the metrics set chosen for inclusion in the pilot, details of the challenges related to achieving a set of standard definitions to support the chosen metric calculations, and the associated analysis of the results.

The report sets out the “statistically significant” relationships found int he study and includes details on those measures which were not, as yet, seen to correlate with outcomes which are deemed critical to product quality and patient safety.

As a result of the learnings gained, ISPE recommended at the conclusion of the report that: ● further study is required to increase the number of sites, technologies, company types and geographies and to collect data over a longer time in order to examine trending patterns, including






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ISPE Quality Metrics Steering TeamMichael Arnold, Pfizer, ISPE Int’l BoardBlair Okita, EMD SeronoJohn Bournas, ISPE President & CEOPeter Carbone, NovartisJacqueline Elbonne, MerckJoseph Famulare, Genentech/Roche, ISPE Int’l BoardKaty George, McKinseyDonna Gulbinski, Bristol-Myers SquibbRobert Matje, Endo/Qualitest, ISPE Int’l BoardElizabeth Blackwood, Johnson & JohnsonJoseph Devito,Teva

ISPE Quality Metrics Core Team

Diane Hagerty, Genentech, Co-chairMairead Goetz, Novartis, Co-chairNuala Calnan, Dublin Institute of TechnologyLaura Cannon, TevaMichael Davidson, PfizerBetsy Fritschel, Johnson & JohnsonSteve Greer, Procter & GambleLorraine Mcclain, TevaMatthew Pearson, GenentechPaul Rutten, McKinseyJoseph Devito,TevaPeggy Speight, Bristol-Myers SquibbVanya Telpis, McKinseyPaul Weninger, PerrigoBryan Winship, MylanChristopher Potter, ISPECarol Winfield, ISPE

more detail on the logistics of gathering product data at an application level, and ● a revised set of five “starter” metrics that should be included in the further study.

The recommended starter metrics are: ● lot acceptance rate (normalized by lots dispositioned) – collected at site level ● lot acceptance rate (normalized by lots dispositioned) – collected at product level within a site ● critical complaints (normalized by packs released) – collected at product level by each product application, not broken down by site ● critical complaints (normalized by packs released) – collected at site level, non-differentiated by product, and ● deviations rate – at site level. [For a comparison of the ISPE starter metrics with the Brookings “consensus” metrics and those proposed in the July 2015 FDA draft guidance see story on pp. 3-10.]

A detailed set of appendices are included in the report that provide the template used for collection, the metrics and their definitions, and full data analysis of the correlations examined.

Making the Dialogue International

The June ISPE/FDA/PQRI conference was co-chaired by OPQ Office of Process and Facilities Acting Director Christine Moore, Genentech’s Famulare and Perrigo’s Yu and covered a broad array of manufacturing regulatory topics across multiple tracks.

Areas of focus at the conference included: ● continuous manufacturing ● measuring process capability ● process validation variability reduction ● lifecycle knowledge management ● supply chain risk management ● change management ● drug shortages ● advanced applications for contamination control ● breakthrough therapies ● data integrity, and ● operational excellence. A session on ICH quality developments provided updates on the Q&As for the API guidelines Q7 (GMPs) and Q11 (CMC development and submission), and the lifecycle management initiative Q12 (see IPQ “Monthly Update” June 2015, pp. 19-29).

Focal points of the conference’s “regulatory insights” track included the OPQ reorganization and the on-going challenges of international harmonization.

A session was dedicated to the quality metrics initiative during the first day of the conference. A special Q&A session followed on day two to discuss the Wave 2 pilot program and provide further information for potential new participants.

In her review of the ISPE quality metrics effort during the first session, metrics team lead Hagerty stressed that the Wave 2 pilot is being designed, in part, to enhance the

understanding of the relationships between the metrics examined during Wave 1. More broadly, she explained, the goal is to provide support for the FDA vision of a more data-driven, flexible and transparent regulatory process and expand industry’s role in achieving it.

Hagerty also stressed the importance that her team is placing on maintaining an international perspective and enabling a data-driven dialogue with other health authorities as well.

The team has talked to representatives from EMA, the UK’s MHRA and the Irish HPRA to gain an understanding of the different views that some of the European regulators are taking in how they are collecting information to inform their risk-based inspection schedules.

While these other health authorities are watching with in-terest and are engaged in the dialogue, Hagerty commented, “they are indicating they are not really looking at moving forward right now with a metrics submission program. However, we want to make sure we are maintaining that dialogue worldwide” and using the industry learnings to help shape it.



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Key Objectives Announced for Wave � Pilot

As the ISPE report indicates, the Wave 1 effort identified some statistically significant relationships. The objective is that the Wave 2 data set will provide more insights across a larger participating group and a better understanding of the relationships.

“We are looking to increase the number of sites, technologies, and geographies that are included in the pilot in order to really help us try to focus on ultimately getting to what are the critical few metrics that really matter and are important to industry,” Hagerty commented.

On the subject of the burden of reporting, Hagerty spoke about the level of difficulty involved for some of the participating organizations in preparing metrics reports at either a site level or at a product level.

In turn, she said, evaluating both the logistics and effort involved across the spectrum of different companies and regulatory pathways will remain a critical focus in the Wave 2 pilot.

For example, she said, “one of the things that we heard from many of the consumer product companies is that they don’t have an ‘application’ number. They might be working off monographs or something different. Wave 2 will be an opportunity to look at that.”

Can Industry Take the Driver’s Seat?

At the June conference, Hagerty expanded further on the “blue sky” vision she had touched on at ISPE’s metrics forum in April.

Behind the quality metrics initiative is “the call to action that many of us have heard Janet Woodcock speak to time and time again: How can we get industry to start really being on the forefront of this and really start driving this rather than feeling that it is FDA pushing industry into it.”

Over time, Hagerty said, industry could help define additional measures that could be included in the reporting process or shared and discussed during inspections, potentially facilitated by FDA’s new inspection protocol effort.

However, she suggested that the real long-term benefits may arise from the development of a stronger industry-led best practice or benchmarking workspace, such as many other industry sectors have. The ISPE pilot, she asserted, has provided a model of this “great exchange of best practice sharing.”

Wave � Building Momentum

During the Wave 2 Q&A session held on Day 2 of the June meeting, Novartis Group Compliance and Audit Head Mairead Goetz explained that the ISPE working group was starting orientation sessions with interested industry companies with the intention of starting the data collection process for Wave 2 in July.

In encouraging firms to consider joining the Wave 2 pilot, Goetz first described the additional benefits to companies that had already participated in Wave 1 in continuing their involvement.

These include trending the Wave 1 metrics over a longer time period, benchmarking on the new Wave 2 metric data, and deepening the cultural analysis of their sites, along with further impacting FDA’s approach (see box on on next page).

For new entrants to the pilot, key benefits include gaining an insight into the implications for centrally reported metric implementation, engagement with peers on best practices, enhanced transparency of site performances, and informing FDA’s decision-making on its reporting expectations (ibid).

It is currently planned that Wave 2 will collect data over the period July through November 2015, at which point the data will be “locked” and the next phase of analysis will begin. Results of the ISPE Wave 2 pilot are expected to be published in 2016.

ISPE’s Wave 2 Pilot Targeted Objectives

• Extend data set to enhance understandings of rela-tionships as further evidence of the benefit of focusing on the “critical few” – Increase the number of sites, technologies, and geog-raphies represented – Continue building data for targeted metric set (or re-fined set based on FDA input)

• Evaluate logistics and effort of gathering product data at an application level

• Continue to develop Quality Culture and process ca-pability measures, tools and dialogue – Facilitate ongoing industry self-development and as-sessment

• Enable continued objective, data driven, dialogue with FDA and other Health Authorities – Moving in parallel with FDA, but a step ahead – Provide further insights to inform FDA decisions during the commentary and safe harbor period

The following are the objectives ISPE has identifiedfor the Wave 2 component of its metrics pilot initiative:


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Woodcock Encourages “Integrated Quality Assessment”

Building on her talk at the April ISPE metrics summit in Baltimore (see IPQ “Monthly Update” April/May 2015, pp. 3-14), in addressing the June conference CDER’s Woodcock expanded on the need for a “mutual embracement of quality” between the agency and industry and commended ISPE for providing a space for this active dialogue.

Woodcock stressed that the current dialogue may be more important to the long-term improvement in quality than the actual quality metrics reported initially to FDA.

In June, she probed deeper into why an integrated assessment of the current “state of quality” is crucial for the agency and its ability to assess risk.

Improved risk assessment, in turn, she stressed, is needed to help support developments in: ● breakthrough therapies ● continuous manufacturing, and ● lifecycle management.

There are trade-offs in authorizing breakthrough therapies, she pointed out, and a deeper understanding of the associated risks is needed to make the manufacturing control vs. patient access assessments.

Woodcock expects a rapid deployment of new continuous

Wave � Benefits for Companies Participating in Wave 1

● Build upon the wave 1 insights of your sites’ performance and create potential to improve performance throughbetter transparency (“what gets measured, gets done”) through:

● Trending on the wave 1 metrics over a longer period● Benchmarking performance on the new wave 2 metrics● Deeper culture analysis through a set of quality culture indicators● Further perspectives on process capability measures state of the industry

● Support the development of common metrics and definitions for the industry by providing feedback onimplications during and after the pilot

● Enable the ongoing dialogue between ISPE and FDA and provide further input to inform the selection of smallset of metrics for the FDA Quality Metrics Initiative

● Continue to set up internal processes and systems to ensure data collection and tracking of the wave 2 metrics

Wave � Benefits for New Participants

● Help influence the industry quality metrics program design and outcome by providing feedback during thepilot on metrics definitions and frequency, culture indicators, and other elements

● Inform the selection of small set of metrics for the FDA Quality metrics initiative (during or after commentaryperiod), by providing input on metrics definitions, ease of data collection and resource requirements, based on actual experience during the pilot effort

● Begin setting up internal processes and systems to ensure you can easily collect data and track thesemetrics

● Develop an early understanding of your site’s performance on these metrics relative to one another andindustry peers

● Create potential to improve performance through better transparency (“what gets measured, gets done”)

● Harmonize your internal metrics definitions (where applicable)

● Gain insight into implications for metrics implementation; facilitate change management dialogue withinternal stakeholders



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manufacturing technologies within the finished dosage form sector and affirmed that the FDA needs to address the challenge of how to adequately risk-assess these new technologies. She pointed out that the Office of Pharmaceutical Quality (OPQ) now includes a new Emerging Technology Team that will take the lead on this.

FDA is also targeting a more sophisticated approach to the assessment of post-approval quality that hinges on better risk understanding across the manufacturing spectrum. Tools such as continuous process verification, statistical analysis and process capability need to be brought to play to help address the current lack of agility in the manufacturing network when there is a marketplace failure, the CDER director said.

Woodcock pointed to how the delays experienced in achieving global regulatory harmonization also continue to present a “drag on the agility” of available resources.

In closing, she affirmed that the quality metrics program plays a potentially important role in improving the ability to predict, and react to, these marketplace events and enable industry to “solve the problems of today in order to better address the opportunities of the future.”

DOWNLOADS FROM THE STORY:

• FDA Quality Metrics Draft Guidance• Business plan

GENENTECH’S DIANE HAGERTY ON LEARNINGS FROM ISPE QUALITY METRICS WAVE 1 PILOT PROGRAM

At the ISPE quality metrics meeting in April, Genentech Global Quality Systems and Processes VP Diane Hagerty , who leads the ISPE Quality Metrics Project Management Team, discussed the lessons learned from the recently completed ISPE Quality Metrics Wave 1 Pilot Program and how they will inform ISPE’s Wave 2 effort. She addressed: ● the background and current regulatory context of the Wave 1 pilot ● Its design, operation and execution ● the participant population ●the data analysis and lessons learned, and ● what ISPE’s plans are for Wave 2.

I first want to extend thanks to all of you that are here, and in particular, I really want to recognize all of the representatives from the companies that participated in the pilot because, indeed, it is those companies that have really made possible all of what we are talking about in these two days. So again, this is a tribute to those folks. I am here on behalf of the entire ISPE quality metrics team. I will cover what will be the high level overview of the pilot, and then, the way we structured this is, we are going to do some deeper dives.

So following me you will have [Vanya Telpis and Paul Rutten from McKinsey], who will do a deeper dive into the details of the pilot and then we will close out with two case studies. Tomorrow, on day two, we will be talking about the quality culture sub-team from ISPE that has also been working in parallel to the pilot. That work is a little bit different because it is outside of this pilot report that will be issued, but we are going to share a lot of that work as well.

Then, as a housekeeping note for everybody here, for all attendees of the conference you will get an advanced read of that final pilot report. It is in a mature draft state at this point, and we are holding [publication of] it because we wanted to have the advantage of the discussions in this summit meeting before we finalize – so that will be coming as well.

In terms of the agenda, what I want to start with is some background and context. I think we probably have a mixed audience. Some of us have been on this journey for quite some time, and others might be relatively new, so I really want to start out with some background for everybody. Then, as I said, I will go into the overview of the ISPE pilot and really talk about the

design and operation of the pilot. I will also talk at high level about the data analysis, the learnings and some next steps.

The Background And Current Regulatory Context Of The Pilot

You heard this today earlier from [FDA’s Ashley Boam] about the vision, and you will see that I have co-opted this. Taking FDA’s vision as really our vision, because I think one of the things about that vision statement, when it is so compelling to your stakeholders that they adopt it, that is the best form of flattery. If we just come back and take those

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words about a ‘maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight,’ I think from an industry perspective we are all signing on for that as well.

Just to bring back that point, that this is a shared vision. In some ways it is hard to believe when I see that quote for Dr. Janet Woodcock, having actually said that ten years ago, that ten years later we are still here and marching on the journey. But for sure, I think this quality metrics program is fitting into that, as Ashley so nicely described earlier this morning.

In terms of FDASIA: this was another big piece of the puzzle coming in as a driver behind the quality metrics program, with FDASIA being issued in 2012. This was really the intent – to assist FDA and industry to reach that vision. Certainly in FDASIA, we also started to see articulation of some other elements, which is really around a legal framework for the FDA to collect information in advance and in lieu of inspections, with quality metrics being one of the key points being talked about in that type of framework. Also looking at how this would inform, and mentally help to inform, the risk-based inspection program as a legal framework where CDER will shift away from inspecting every two years to a formally codified risk-based inspection program.

This is really the overall timeline that some of the activities have occurred. With FDASIA being issued in 2012, the first federal register notice on quality metrics was issued in February 2013. We had initial industry responses coming out shortly after that, and then we started kicking off a number of teams within industry and certainly within FDA as well, I would imagine, were gearing up.

We had a number of white papers that were submitted to the FDA at the end of December of 2013, and from there forward, we had the Brookings Institution meeting, which was requested by FDA. I think that is a critical point on the timeline because we often talk about the “consensus set of metrics” that came out of the Brookings meeting. You will see that referenced later in my talk.

Then from an ISPE perspective, and that Brookings meeting which was held in May 2014, we kicked off the ISPE pilot in June of 2014 and subsequent to that, in September of 2014, we had FDA coming forward with their potential set of metrics that they are interested in, which also informed the dialogue.

Subsequently, at the backend of that year, part of this dialogue had also been about the quality culture aspect. And a lot of other work going on within other industry teams, particular PDA, has been focused in supporting the dialogue around the quality culture aspect within two of their meetings. We also have Xavier University involved across quality culture and some other initiatives.

This brings us to where we are right now with our April Quality Metrics Summit here in Baltimore to talk deeply about


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the pilot. This is really the Wave 1 output of the pilot. We are already actively working on Wave 2 and hope to be able to announce that kick off in June, so that will be coming forward. As Ashley described, all of this work was going on in parallel to the draft guidance coming forward from FDA.

The overall intent of the ISPE quality metrics program was to help, through discussions across the industry and regulators, in coming up with a clearly defined set of metrics that will allow consistent reporting across sites. We are looking for things that can be objective and meaningful, and easy to capture and report – recognizing that they need to be normalized based on factors such as process, and acknowledged differences.

Clearly a hallmark to keep sight of, within the quality metrics program, is that we want to be really focused on driving acceptable behaviors, and not unwanted behaviors….

The Design, Operation and Execution of the Pilot

In terms of the 2013 ISPE white paper, one of the recommendations from ISPE was to conduct the pilot in order to flesh out definitions and approach.

Initially that white paper, the ISPE position, was very focused on looking first on “site-based metrics” and how we might meet the need for “product-based metrics” later, and part of that motivation was just based on sheer volume – from an industry perspective, thinking of the sheer volume of data that may be coming into FDA. If you have site-based data coming in, with approximately 12,000 API sites in the FDA database – versus coming in by product – you can see that would be a whole other level of magnitude coming in at a product-level versus a site-level. This was some of the early framing that we were taking into the design of the pilot.

As we further that, and look at the objectives of the pilot, the objectives were multiple-fold. First and foremost was to test a set of metrics based on the industry and FDA input to date. Again, this was kicking off in June [2014] and we had just come from the Brookings meeting, so that informed a lot of what we went forward with in the pilot metrics set.

Another big task of this pilot was to test the ability to get to a harmonized set of definitions. I think we will talk a lot about that later. It can be very difficult to get to a common set of definitions and describe them in such a way that they can be executed in a harmonized manner.

We were also looking to test the feasibility of data collection across different companies. Also, we included in the pilot, qualitative surveys related to quality culture and the use of process capability tools. Again, we saw these as important as leading indicators, but [in wave 1] we went after a qualitative approach to get more of an assessment of these measures rather than specific metrics.

We were pleased to partner with McKinsey for the conduct of the pilot as McKinsey brings a great depth of experience in this space. They have been conducting their POBOS benchmarking of quality across the pharmaceutical industry for many years. So, we were pleased to leverage that experience and their guidance as we moved forward with this draft set of metrics and the collection tools to work with the participating companies.

The other aspect that was important about partnering with McKinsey was it enabled us to have an independent third party receiver of the data – so that the data from all of the participating companies could come in, in a confidential manner, be maintained in a confidential manner, and then as part of the pilot reports that are going out to the individual companies, they will also have the benefit of seeing some benchmarking data. For each of those companies participating in the pilot, they will see their own data and then they will see where they land in terms of benchmarks across the industry average, as well as within their technology peers.

First and foremost, the intent of this pilot was to inform the ongoing dialogue with FDA in the quality metrics space. What we were looking for was to be data driven, very objective and experiential with the pilot, and to have this come into the dialogue for the industry.


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The Pilot Participant Population

This is an overview of the sample set that was included in the pilot. So you will see that there are eighteen participating companies. Across those eighteen companies, we have forty four different sites and various technologies. I am not going to go through each of the slides in detail here, but you will see some of that demographic information.

In terms of how that pilot data set was split out, you will see that we have a good spread across different technologies. We also have a good spread across the different types of products – so Rx, generic, consumer health, CMOs, and laboratories. We also have a fairly good split by region. You will see that in terms of the size of the companies, we are skewed towards those larger companies at this point with the [Wave 1] pilot data set.

The Metrics Set and the Importance of Definitions

In terms of the set of metrics that were included in the pilot setting, you have a handout with the details of those definitions – and as we move into the breakout sessions over the next two days, those definitions are included in that handout for your reference. Let me just briefly preview what we included in that pilot set of metrics. You will see that there are twelve metrics that were included. We have quantitative metrics where we are gathering quantitative data related to some of these measures.

You will see that the first four of those that are listed there are highlighted in blue. Again, coming out of that Brookings meeting in May [2014], it was those first four that were really identified as the industry consensus metrics at that point, so they were included.

You will also see that, as I talked about briefly, initially the ISPE purpose was to focus on site-based metrics. We were taking a lot of input as we became ready to start the pilot and understood that the FDA had very strong interest in product-based measures as well. You will see that there were a number of quality metrics – those that are highlighted with that yellow symbol – that were collected at a site-level as well as at a product-level.

Then we also included some technology-specific metrics. What you will see there are a couple of measures that were really specific to the sterile manufacturing processes. Then, as I had mentioned, we included additional survey-based metrics for process capability and quality culture.


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Also, over the course of collecting the data, because of the way the data was collected, we collected component measures of each of these metrics. So after the fact as we got to analyzing the data, we recognized that there were two more quantitative metrics that we were able to look at in terms of potential correlations. That was deviation rate and also incoming material OOS rate.

I also want to acknowledge that a lot of dialogue was going on in a really open manner between all the companies that were participating in the pilot. Part of how we got to that incoming material OOS rate as one of those metrics was in fact specifically based on

feedback we received from companies – that the way we had structured that initial metric was too difficult. And so we had to split up the separate metric related to incoming material OOS.

Then just to mention quality culture, we will touch on it here in terms of how we realized the quality culture survey in the pilot. But we are also going to have much more detailed discussions about the parallel efforts of the quality culture sub-team tomorrow in day two.

This is the overall pilot timeline. And again I am not going to go through this in detail, but what I want to draw your attention to is the bottom swim-lane here around communication. As the pilot was moving along, we were having a lot of dialogue with the participating companies. We had a ‘pilot leads’ call, with lead representatives from each of the companies that were involved in the pilot, and we got together periodically to really check in with the companies to understand how the pilot was going – get the questions, feedback and comments coming in.

We had four calls over the course of the pilot with those pilot leads. We also then did two calls with the senior executives, so the senior quality leaders for those companies that were involved in the pilot, to get their perspective and their feedback – to hear from them in terms of their thoughts and input that they would like to bring forward, as the pilot was about having that dialogue across industry and FDA.

You will also see that we had two very detailed meetings with FDA. We had been in constant dialogue with FDA throughout the conduct of the pilot to give them an update in terms of where we were with status, but we also appreciated time from the FDA working group on quality metrics. We were able to go in for two very detailed meetings to share on the output from the pilot, and share some of the data that we were seeing, as well as really have some dialogue about findings – that was really valuable as well.


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Lessons and Key Takeaways

Let me move forward at a high level and recount some of the lessons and some of the key takeaways that we had from the pilot.

First of all, I want to focus on the data collection effort. One of the things with the setup of the pilot we were able to do, and that we wanted to be really deliberate in the structure of the pilot, was to gather information about what the experience was for the companies to gather the data and to test that data.

I think one of our key takeaways from this was that we saw that standardizing definitions across companies is feasible. However, and there is a big however there, some of these learnings were that the definitions had to be really precise and really exact in order to avoid multiple interpretations. Getting to that level of definition was a constant iterative dialogue to answer the questions to get there.

For sure, what we also see, and I think that Ashley also spoke about this: that getting to the standardized definitions will represent incremental work for companies. This is really recognizing that, as Ashley said, there is not one common metric across all companies, across all processes. There is value to getting to a standardized set of metrics, but with that there will be incremental work for firms.

We also recognize that depending on where firms are in the quality metrics journey, they may have advanced, they may have found some other things that are more pertinent to their business. So in some cases we may see that the metrics reporting program for FDA may result in some redundancy in metric reporting for firms as they continue their own metrics program while at the same time reporting metrics to FDA. We have also talked about the importance of, and this was also recognized by Ashley, being able to have a commentary on the data points, which is really necessary for the interpretation and analysis.

Site-Level vs. Product- Level Metrics

Another area that we looked at was the ability to collect these metrics either by site or by product. What we have discovered, and what came forward from the pilot, is that what we see right now is that only a few companies are aggregating metrics across the entire supply chain. In many cases, we have companies that are reporting their metrics right now at a site-level. It will depend on the metrics: some of the metrics are more easily reported at a product-level so it depends on the metric chosen.

One of the things that will be, I think, an evolution in the industry journey is how do we aggregate these metrics across the supply chain. So consider, internal providers, external providers, contract laboratories: that was a key learning for the pilot.

Another aspect here is that we heavily attribute the success of the pilot to a couple of things. One is that open dialogue between the giving and the receiving sites, the collaboration involved in that, and the support of the McKinsey Team. Being able to leverage the McKinsey experience and capability and the means by which the McKinsey team undertook detailed discussions with every firm and every site that was involved in the pilot. They spent a lot of time answering questions and helping to look at the data, iteratively looking at that data, to make sure it was clean and appropriate to be proceeded with in the pilot.

Potential Burden of Reporting

Lastly, a further aspect that we looked at was around estimating the potential burden of reporting.

With this, we were very deliberate to look at gathering, from all of the companies in the pilot, the amount of time it took them to collect this pilot set of twelve metrics. We did a rough calculation – so it was, on average, taking the sites around ninety hours [per site] to collect that data. Based on that, we did the calculations to indicate that it could potential cost the industry thirty-five million dollars annually.


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We did recognize, as we talked about this with firms, that was maybe a conservative estimate. I think there are a couple of differences that are really important to note about the pilot. One was the concept that we had lower stakes on the data. We had the ability within a pilot to go with the ‘good enough data’ and certainly firms will take a different approach when they are formally submitting data to FDA. So that was one factor.

Another of the factors was that there was no time spent in the internal review and management review of that data because we were in a pilot situation. I think we are going to have a different framework as companies formally submit.

We also heard a lot of commentary from firms that, with being able to collect this common set of metrics, there will likely be changes to the IT systems and pulling side of this data that could result in costs related to either new or modified IT systems to collect, analyze and store that data.

I had mentioned previously that in the pilot we were again looking at the data provided by site. It was not necessarily through the full supply chain.

We also want to recognize that, in the pilot, we had companies that were voluntary companies. They had mature systems and capabilities. So we want to keep thinking about how this might look like for industry as a whole.

Another important point, and this came up in one of the questions earlier this morning, is that the pilot did not include a process to reconcile and maintain that data for verification during inspection. So that will be another aspect that will be important for firms.

I think as we look at this, and the one number we could actually calculate based on hard data in the pilot was the ninety hours reporting burden that we estimated. We went back and did some interviewing with other firms and we certainly heard that this estimate might be an underestimate. It could even be in the order of one hundred million dollars plus. Our perspective on this is not to focus on a number. This is more relative in terms of thinking about this initiative.

Certainly, whatever form the final program will take will have a big influence on what that reporting burden might be. So, as we think about that reporting burden, it is also important to think about what the counterbalance to that potential burden for industry is. I think we have already heard a lot this morning, that there are incentives for firms, if we can move to a transparent risk-based inspection program. This can also be a positive counterbalance to that burden discussion.

An Overview of the Data Analysis

Let me move on with the data analysis. I am going to go at a high level here for the overview and turn the details over to Vanya and Paul. One of the things we did, and this is really a depiction of the various metrics that were included in the pilot, is that we looked for relationships across each of these independent variables. What you will see here in the slide, where you see the darker lines showing you connections, this is where the pilot data actually showed us that there were correlations between these different measures.

Let me just move forward and summarize this. When we looked at this data, what we saw is that we had a group of metrics where we saw some demonstrated relationships between the data. That was in critical complaints, lot acceptance rate, deviations rate, quality culture, and deviations recurrence. While those relationships are statistically significant for the pilot sample, we do believe that they require some further testing in order to better understand those relationships. Another very important point to keep in mind is that while they are making a demonstrated relationship, that does not necessarily mean there is a causal relationship to those different metrics.

We also interestingly saw in the pilot sample, some metrics that did not have clear relationships and some of that was a bit surprising. One of those that was surprising to us that did not demonstrate a relationship in the pilot data set was in the area of OOS. Also we did not see correlations with CAPA effectiveness, APR time, and stability failures. We do think there are some limitations based on the size of the initial dataset, so we are certainly interested in looking at that in the Wave 2 Pilot.




For the technology specific metrics, these are those related to the sterile manufacturing. We had a small sample size here, so we were not able to test a lot of statistical parameters. That data also initially shows that it was not differentiated at all between sites for those two measures.

Relationships between Quality Culture and the Metrics

Let me speak now a little about quality culture. We did include a quality culture survey in the pilot. The purpose of that quality culture survey was not to test out a measure of quality culture, rather it was to utilize a standardized approach – and this is where we were leveraging heavily from McKinsey. What we were really interested in with this was to have an instrument to test or measure quality culture so that we could look for the relationships: that was the primary driver here.

The way that this was conducted is that it was measured through an all-employee survey. It was really looking to capture the attitudes toward quality at the shop-floor level – and it is that shop-floor level where that is really important. You will see that we had over ten thousand respondents to this survey across thirty-seven sites included in the pilot. So, there was a huge amount of information and data coming forward in that quality culture survey.

As mentioned, the quality culture survey we were using was leveraged from a survey that McKinsey currently uses in their POBOS benchmarking process. We took that survey and slimmed it down to fifteen questions across five

Process Capability Survey

• Process capability measurements are being adopted in the industry though there is no consistency yet in approach used.

• Usage: 95% of all sites measure state of control during production process, most apply to all products. Some exclude products based on risk approach to customer and importance for business.

• Metrics: Trending is most widely used – by 69% of sites. CpK, PpK, and tolerance levels used less often – by 39% and 22% of sites respec-tively.

• Parameters measured: 91% of sites measure state of control through CQA, while only 56% on IPC and 61% on CPP


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different parameters, and then we utilized that to get to one overall score for each of the sites. Then that score was used to look at relationships between quality culture and the different other measures and metrics.

Interestingly, and again this was a little bit surprising because we were taking that tool and streamlining it, was that even with that streamlined tool, we saw very strong correlations with quality culture and some of those metrics. That was quite interesting and useful. I think it also serves to validate the ongoing dialogue with the importance of quality culture within a holistic view of the quality metrics program.

A Qualitative Assessment of Process Capability

I also want to touch briefly on process capability. In this survey what we did was to include some qualitative questions where we were trying to get more of a baseline understanding of what is going on across sites and across industry related to process capability.

I think what we have seen with that data is that process capability measurements are being adopted across industry, but there is certainly no consistency in the approach being used. That may actually be okay, because I think that these process capability measures need to be specific to the different types of manufacturing operations going on.

We did find that 95% of the sites measured the state of control during the production process, and they are doing this, mostly, across all of the products at their sites. Some sites do exclude products based on a risk-based approach, either based on the customer or the importance to the business. In terms of metrics that are currently being utilized in the process capabilities space, we saw that trending was most widely used across 69% of the sites. We saw that CpK and PpK tolerance intervals were being used less often – in the order of 39% and 22% respectively – across the sites in the pilot.

In terms of parameters measured, you will see that the majority of sites are measuring their process capability against the critical quality attributes (CQAs), and then to a lesser extent across in-process controls as well as critical process parameters (CPPs).

The Next Steps: A Potential Starter Set of Metrics

This is really an overview. What we tried to do here was summarize how we looked at this set of twelve metrics.

First was to look at the relationships that were identified between these metrics. Secondly, how much time did it take to collect these metrics and how difficult was it to collect the metrics? The other aspect that you will see is how, with some of these metrics, we have had inordinately lengthy discussions about definitions. From this, our conclusion was that it would take more time to get those definitions right. So you will see that cited on the right hand column….

Looking at that summary slide I have just shown you, basically what we came away with was a recommendation for a potential starter set of metrics. What we came back with, and this was based on looking at that summary in terms of parameters such as the ease of collection in order to balance against burden – looking at where we saw correlations and insights: I think the position that ISPE is taking coming forward out of the Wave 1 pilot is that we see a potential starter set of metrics that are relatively well established across industry.

We would recommend that this would include lot acceptance rate, which is normalized by lot disposition, that would be collected at the site-level – but also looking at that lot acceptance rate by differentiating it by product within the site. We also saw a lot of correlations across critical complaints, and so we would recommend that this metric be collected at a product-level, not broken down by sites. However, some of the feedback we also received on the pilot is that many firms are gathering complaint rates on a corporate level. We would also recommend including critical complaints at a site-level not differentiated by product. What we mean here is to look at, of those critical complaints, how many of those are being sent out to sites for investigations.

We also have included deviations rate at a site-level.




In Conclusion

From what we see here we note that it is feasible to collect a standard set of metrics across companies. And we would recommend that we start with this relatively well established set of metrics. That will really serve as a basis to learn and build capabilities across both industry and FDA.

Also in terms of some of the emerging recommendations, we see in the pilot the continuing emphasis on the importance of quality culture, the importance of process capability. However, we believe that those are measures that are not ready for reporting. We believe that they are best utilized internally within the company. These are often measures that are being used to drive continuous improvement within the companies, which is important to preserve.

We also see that there may be the opportunity to look at some of these measures in a situation where we have the ability to have a dialogue between the FDA or the health authority and the company. These are things that might be more amenable for the new inspection protocol approach that Ashley had mentioned.

I want to close with – we have seen a lot of value in the Wave 1 pilot. We see a lot of value into the Wave 2 of the pilot, and we are targeting a kick off with the Wave 2 in June of 2015. A couple of the things we would like to look at in Wave 2 of the pilot are first and foremost to expand the number and types of companies participating in the pilot. We will then also be able to build on the initial Wave 1 pilot set and do its continuation of building the data around the targeted metrics set or a slightly different metrics set depending on what input we have received.

It will certainly give us the ability to continue to test for relationships. As we had mentioned we were surprised that we did not see relationships in some areas, so we would like to continue to look at that. We can also continue to look at future measures that may be indicative. This may be quality culture measures. It may be things that may also help us be more predictive or more related to drug shortages. There is a lot of opportunity with that going forward in Wave 2.

I want to close with a ‘blue sky thinking’ of quality metrics vision and where this might take us. It needs to be a step-wise learning journey for both FDA and industry as we move forward.

One of the potential ways we can look at this is to start out with a starker set of methods that are important to FDA. We talked about looking at additional measures that are in need of more of a discussion during an inspection or where you


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have an ability to have a dialogue. With that, then perhaps we can look at additional measures of reducing regulatory oversight. This might be means where we can get some of a reduction for post-approval supplements that Ashley had talked about further.

I think longer term as we think about this from an industry perspective, what we really would like to think about is how do we move from FDA, someone leading this initiative, to putting industry in front of this – to creating a workspace where industry can come together to continue to iterate on metrics – utilize that as a mechanism to foster learning across the industry, helping industry mature. I think the other aspect of this that is important to think about is to think around the landscape beyond FDA’s interest in quality metrics. FDA is very often leading for many of the other worldwide health authorities. This type of aspect might help enable a space where companies will be able to provide access to other health authorities to look at these metrics.

One of the things we want to be mindful of and maybe want to avoid is that we longer term have a divergence of health authority use on quality metrics, and starting out programs where they are asking for a number of metrics that are not harmonized across a regulatory landscape.

Ultimately what we believe here is that we can use this. This is really a means of getting the potential benefit of achieving transparency of quality performance across the industry. I think that will help us make the shift towards quality being a competitive advantage for companies.

I want to close with a huge thank you and a huge acknowledgement. This is a collective concerted effort across industry. We cannot emphasize enough how much we appreciate all of the companies that precipitated in the plot. I want to thank FDA for the ongoing dialogue and input along the way, certainly want to recognize our McKinsey partners, and thank all of the ISPE quality metrics team members that had been meeting on a weekly basis for over a year to make sure the pilot was really executed and delivered in a timely fashion to be able to input to the industry dialogue at this point.

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JAPAN 2 15

9-10 November 2015 • Tokyo Marriott Hotel, Tokyo, Japan

Organized by CASSS and Supported by the Pharmaceuticals and Medical Devices Agency, Japan and the Japan Pharmaceutical Manufacturers Association

SCANto browseCASSS forprogram

updates at casss.org

SCAN to browseCASSS for forum

updates at casss.orgOrganized by CASSS An International Separation Science Society

The Mayflower Hotel, Washington, D.C.

January 26-28, 2016

20th Symposium on the Interface of Regulatory and Analytical Sciences for Biotechnology Health Products

Topics:• Cell Line Selection and Control of Product Consistency during

Cell Cultivation – Myths, Risks and Best Practices• Change Happens: Technical and Regulatory Considerations

for Pharmaceutical Product Lifecycle Management

Abstract Submission Deadline:November 18, 2015 for poster presentations

Symposium Co-Chairs:

Michael Kennedy, CBER, FDAJuhong Liu, CDER, FDABrian K. Nunnally, Biogen

CELEBRATING 20 YEARS

January 25, 2016




Relationship with Excipient Providers Drawing Increasing Pharma Attention, BMS Exec Stresses; IPEC Urges Regulatory Pathway for New Excipients in GDUFA/PDUFA Comments

INTERNATIONAL

An important component in the ability of pharmaceutical innovators to bring their new products to market in the eclipsed timelines in which they need to function will be their relationship with excipient providers, a top manufacturing executive from Bristol-Myers Squibb (BMS) stressed to participants at the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas)/ExcipientFest conference in San Juan, Puerto Rico in late April.

Providing the final keynote talk at the conference, BMS Pharmaceutical Operations Senior VP Ricardo Zayas made a compelling case for why this relationship has become increasingly important in pharmaceutical product development and to the financial viability of the companies involved. Zayas has responsibility for the strategic and operational leadership for BMS’ global supply chain.

Explaining that development to launch speed “is the single most important imperative right now” for an innovator company like BMS, Zayas stressed the need “now more than ever” to work with excipient suppliers “to reduce this.”

He urged the excipient makers at the IPEC conference to “internalize” the lesson from products like Gilead’s Hep-C treatment Solvadi, for which good risk management and formulation work helped cut the normal launch cycle time in half, allowing the product to be first in class and generate almost $10 billion in first-year sales.

“This is the future. This is where we are headed,” the BMS exec said. “Development to launch is going to be the single most important differentiator going forward. It is very important. And our work with you folks is very important to be able to get us there.”

Drug Quality and Process Variability Also at Issue

Also raising the profile of this partnership at pharma companies is the growing recognition of the criticality of excipients in drug product quality, processability and stability, and, in turn, in controlling process variability, Zayas said.

With relevance to the FDA/industry dialogue around the agency’s metrics initiative (story on p. 3-27), Zayas explained

why he views “right first time” as the most important metric in managing a pharmaceutical manufacturing facility and how excipient reliability is integral.

Inherent variability in the process causes deviation investigations and leads to “all the re’s: rejects, reworks, reprocessing, retesting, reinspections, repackaging,” which result in backorders, recalls, major expenses and lost revenue. In turn, “a big enabler” to controlling variability in a process is communicating with the excipient suppliers, Zayas stressed.

Pharmaceutical manufacturing has become increasingly complex, and sustainability, which is a competitive advantage, requires a partnership between excipient vendors and end users.

“We want to partner,” the BMS exec advised the IPEC forum participants. “Manufacturing groups are going to work more in concert with late-stage drug development to really develop drug products that are sustainable and robust. You folks play a very important role in that, but it is important that you start speaking this language.”

The old pharma view of excipients as “inert materials with some functionality” is changing to viewing them and the innovative technologies they are deploying as “enablers of product success,” he affirmed.

Excipients as “Enablers” has Caught Regulator Attention

Zayas began his presentation at the IPEC-Americas/ExcipientFest conference with a review of the “past, present and future” of pharmaceutical manufacturing, which helped frame the discussion of excipients that followed in his talk.

In the latter part, the BMS exec provided specific examples of the increasingly important role innovative excipient technology needs to play in new product development and discussed why partnership and collaboration is important and what can be done to “really maximize the value” of the relationships. [Zayas’ remarks at the conference are included in full below.]

Zayas took time after his presentation to field a couple of significant questions posed to him by


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conference participants with relevance to IPEC’s efforts in the novel excipient and supply chain arenas.

An audience member asked for his view on “how to translate” the import of his remarks “not just to ourselves,” the excipient suppliers, “but also to the agencies” so that they can “understand and accept the challenges.”

The BMS exec highlighted the thrust of the question, reiterating the emphasis he had put on excipients as “enablers.”

“I think you will find that the agency is much more open to these kinds of conversations now than when they were in the past,” he said. “I think they have realized that a lot of these excipients – both the ones that have existed for a while, and the new ones that are coming out onto the market – are enablers. Because let’s remember that one of the primary purposes of the agency is to make sure that the drugs that people use are safe. But the other purpose is that they actually get these drugs.”

He offered a salient example he had also referenced in his talk. “If there is a drug out there that uses a new application for an old excipient as an enabler to be able to cure genotype 2 Hep C, they are going to listen and they are listening.”

As he had in his presentation, Zayas stressed again that the pharmaceutical industry is “going through a big second round of development where a lot of very important typically unmet needs are going to be filled over the next ten or twenty years. So the agency is listening a lot more.”

The operations leader also emphasized the desirability of starting to work with the agency on these pivotal formulation concerns early in the process.

“You don’t want to wait until a year before launch, or during filing, to have this kind of discussion. You want to have these discussions in early Phase 2 and tell them what you are thinking and prime them for this, because they don’t like surprises.”

The willingness of the regulators to listen “because of the drugs that are coming onto the market” and speaking to the “right people very early in the process” are the key factors in having “a successful conversation with them,” he summarized.

Colorcon Global Regulatory Affairs Director David Schoneker, who has been a prominent spokesperson for IPEC in the industry/regulator novel excipient discussions, expressed his appreciation to Zayas for highlighting the issues that “many of us have

been talking about for years.”

In view of the importance of the concepts the BMS exec was espousing, Schoneker pointed to concern about “a disconnect, at least in a lot of companies out there, between these concepts and the purchasing department, and in terms of what R&D sees their needs are versus the purchasing department,” which is preoccupied with obtaining “a 20% price reduction.” He asked Zayas “what training you guys do at BMS with your purchasing department to get them on board with this wavelength.”

Zayas quipped that the subject was a “sensitive” one, referencing the 75-page document he had to read to learn how to approve purchase orders when he joined BMS three years earlier.

He highlighted the importance BMS places on the global purchasing organization being involved alongside the manufacturing and R&D departments in the early development phase.

“I am responsible for manufacturing. I have a counterpart that is responsible for development, both early and late stage. We work very closely together. Our single most important imperative is what I said a while ago – reduce development to launch, whether it is two months or twenty years.”

In the case of a BMS product recently put in line for breakthrough therapy status, the cycle time from development to launch suddenly dropped by a year, creating “a very significant challenge” for the company.

The steering committee overseeing the process includes “one of the highest level people in the global purchasing organization, precisely because of that…strategic imperative.” Zayas predicted this dynamic will be more and more prevalent among pharma companies.

IPEC Makes Case for New Excipient Regulatory Pathway in GDUFA & PDUFA Comments

As Schoneker alluded to in his question, Zayas’ remarks and the examples he provided in his presentation are highly relevant to the concerns that IPEC has been expressing around the regulatory constraints to deployment of the new and coprocessed excipients that are needed to facilitate the development of the more complex, powerful and patient-friendly pharmaceutical products on the horizon.

IPEC-Americas has been working with the pharma-based IQ Consortium to develop a proposal for establishing a viable regulatory pathway for new or modified excipients that would be compelling to FDA (see IPQ “Monthly Update” June 2014, pp.



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14-18).

An independent FDA safety review system for excipients that would foster their being designed and/or adapted to meet the increasingly sophisticated demands of formulating pharmaceuticals has been an objective of IPEC’s since its formation two decades ago.

In turn, the frustrations of pharmaceutical manufacturers of not having new excipients in their formulation toolbox has forced the concern onto the front burner of the IQ Consortium, formed to help “advance science-based and scientifically-driven standards and regulations for pharmaceutical and biotechnology products” (see IPQ “Monthly Update, June 2012, pp. 31-38).

IPEC-Americas has been explaining the problem and making the case for a more open regulatory pathway for new excipients in responding to FDA’s request for input on the reauthorization of its Generic Drug User Feed Amendments of 2012 (GDUFA) and Prescription Drug User Fee Act of 2002 (PDUFA).

Comments on behalf of the association were made by Colorcon Global Regulatory Affairs Director David Schoneker at the public meetings held at FDA headquarters on GDUFA in June and PDUFA in July, and more extensive written comments were submitted in both contexts in July and August, respectively.

The written comments highlight why excipient innovation is an increasingly important factor in advancing drug development and manufacturing science and the impediments posed by the current regulatory review process to bringing them forward.

A framework is then proposed for establishing a new regulatory process that would provide for an independent review and qualification of excipients by FDA, helping to alleviate these impediments and free up excipient development and pharma use.

The “Novel” Umbrella is Wide

IPEC’s concern with novel excipients is heightened by the breadth of the different types of materials and compositions that fall under that umbrella – namely, any that have not been used in an approved drug product in the US, according to the agency’s Inactive Ingredient Database (IID) listings.

Along with new chemical entity excipients, which are typically only used in innovator drugs, these include excipients that are new grades, chemically modified, co-processed, or in higher levels or new routes of administration.

Schoneker commented to IPQ that IPEC envisions

that the excipient qualification process under consideration would only get used “once in a while” for a true new chemical entity type of excipient because of the investment involved. Where they “really see it being used,” he said, is in the area of co-processed excipients and where levels and routes of administration come into play.

In this arena, he noted, “there is this same level of need, but it is much simpler situation. You don’t need a lot of data, or the data may already exist in many cases. It is just a matter of packaging it so that you can get a review.” While a review/qualification process would be increasingly used in this context, “if we don’t have a process than those materials and those uses also suffer in a big way.”

Reflective of BMS exec Zayas remarks at the IPEC-Americas/ExcipientFest conference, Schonecker points out that the “stars are now aligned” to move forward, given CDER’s focus on the issues around low solubility/permeability actives, pediatric formulations, QbD and advanced manufacturing technologies and its awareness of the role of excipients in helping address them. “What we are trying to do is find a reasonable way to facilitate that,” he said.

Biomarker Qualification Process As Model

Helping to inform the IPEC-Americas’ comments was a meeting in early June at which IPEC and IQ representatives met with a large group of FDA toxicology and policy officials to discuss the concept of an independent safety review of novel excipients and what would need to be addressed to move the proposal forward. Consideration was also given to how user fees could be deployed to make the process more effective.

Understanding that the goal was not an independent approval process for excipients but rather a preliminary review or qualification of the relevant safety data, FDA officials at the meeting pointed out that there were some similarities with agency’s relatively new biomarker qualification program and suggested that IPEC and IQ reference that in refining their proposal.

As in the novel excipient case, the biomarker program reflects the resistance to putting something new into a drug application that could affect its approval status without some prequalification by the agency.

Companies can apply for a biomarker qualification and the request goes to a multidisciplinary group of experts that FDA puts together. Based on the review of the company’s submission, the group responds whether or not they believe




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the biomarker is qualified for the intended use that has been proposed. If judged favorably, the biomarker is then listed on the FDA’s biomarker qualification program website as one that others can then also use for a similar purpose.

The review by the IPEC/IQ team participants concurred that there was a lot of relevancy and similarity to what they have been recommending for novel excipients and that the biomarkers process could help substantiate it.

As in the biomarker case, drug sponsors do not want to be the first to test the waters with a new excipient. On the other hand, IPEC and IQ have been advocating that a preliminary screening process would be viable, where the novel excipient would still get “approved” in the context of a particular drug product but with the barriers removed by the determination that there is no safety concern related to its use in this particular route of administration and exposure level.

“This type of system,” IPEC-Americas asserted in its comments, “would give drug developers confidence to include novel excipients in drug products and facilitate innovation.”

The association proposed that novel excipient safety information, including studies and bridging arguments, could be provided in Type IV or V DMFs.

In turn, “a GDUFA/PDUFA type user fee system could provide resources to FDA to perform these independent safety assessments or qualifications.” A list of excipients could then be published that could be considered “qualified” for specific intended uses and level in pharmaceutical products based on the independent safety assessments.

IPEC-Americas said that it will continue reviewing the biomarker qualification process as a model for the novel excipient review process, and will be working with the IQ Consortium and GPhA to identify the adjustments needed.

The lack of user fees in the biomarker case, however, has surfaced as a concern for the IPEC/IQ group in reviewing it as a model. The IPEC comments to FDA suggest that the novel excipient safety review process “would need to include some type of time-line commitment similar to what is involved in GDUFA goal time-lines,” which are driven by the user fees.

The industry groups have been making clear in their comments and meetings with the agency that, although there is an existing pathway for getting novel excipients approved through the current drug review process, it is not generally viable. In turn, they point out, excipient innovation is pivotal to the advancement of the objectives of quality by design and continuous manufacturing and in addressing the formulation and solubility challenges that are now on the table.

Solving those issues and improving and modernizing drug development, IPEC and IQ is saying, rests on having a pathway that facilitates not only the use of the new materials, but an economic model that incents a company to continue to develop them. They note that, without this pathway and more certainty of usage, even large excipient manufacturers with the technological know-how are increasingly unwillingly to make the large investment required.

IPEC’s GDUFA and PDUFA comments conclude by expressing the association’s desire to collaborate with FDA in further defining what a viable excipient qualification

IPEC-Americas Proposal for Excipient Review Presented in GDUFA & PDUFA CommentsThe following is a summary by IPEC-Americas of the key points included in its comments to FDA on the PDUFA reauthorization. In its comments, IPEC-Americas explained the breadth of the types of excipients in the “novel” classification, why they are vital to the pharmaceutical industry and why an independent FDA safety review/classification process is needed for novel excipients outside of the normal drug approval pro-cessto spur their development and use. IPEC-America’s GDUFA comments are very similar. Links to the full comments submitted to FDA on both GDUFA and PDUFA are provided below.

The FDA defines new or novel excipients in their Guidance on Nonclinical Studies for the Safety

Evaluation of Pharmaceutical Excipients and this definition includes the following types of novel excipients:

• New co-processed excipients made from two or more previously approved excipients (usually manufacturedusing a physical process such as spray drying or melt extrusion)




• New uses of an existing excipient – examples would be: Higher level of use in a previously used route of administration Use in a new route of administration

• New chemically modified grades of an existing excipient (minor changes to existing excipient)

• New chemical entity excipients (NCEs) – these tend to be what people think of when discussing novel excipients. However the other types mentioned above are also considered to be novel excipients from a regulatory perspective.

The degree of newness for different types of novel excipients will influence the amount of safety data required to complete an appropriate assessment.

Novel excipients may be one important key to drug product improvements. They may address the following issues:

• patient compliance – through, for example, advancement of formulation of more patient-friendly dosage forms

• development of high-quality drug products – through, for example, modification of drug plasma profiles

• advancement of manufacturing science for drug products – through, for example, enabling or facilitation of continuous manufacturing or other advanced manufacturing methods for drug products

Currently neither pharmaceutical companies (as excipient users) nor excipient manufacturers have incentives to use or develop novel excipients which can produce all three potential improvements discussed above.

Pharmaceutical companies are generally unwilling to risk the use of novel excipients because of the regulatory uncertainty of the current process to get them approved in their formulation which can result in delays in approval of their application. Novel excipients could be an important factor in controlling costs of drug development since formulators might then be able to use the “best tool (excipient) for the job” instead of having to formulate around an approved but sub-optimal excipient. In some cases, certain drug products may not be able to be developed using traditional excipients and novel excipients may be needed to resolve various physical issues with APIs such as poor solubility and permeability.

In the case of excipient manufacturers, it follows that if their customers are unwilling to risk using novel excipients, there is little incentive to develop them. This can, and in some cases does result in stagnating market growth and innovation.

In the current state of affairs, there is no mechanism for evaluation of excipients alone – they are only evaluated as part of drug products in NDAs and ANDAs. This result sometimes leads to drug products which are “good enough” but which may not be optimal.

IPEC-Americas has proposed to FDA that it adopt a new regulatory review or qualification process for novel excipients which provides for stand-alone (independent) review and qualification of excipients by the agency. The intent would be for this new regulatory review or qualification to help mitigate the uncertainty associated with novel excipient use.

It is important to note that IPEC-Americas has not suggested that novel excipients would or should be “approved” outside of the drug approval process, but rather that there could be preliminary safety and qualification assessments independent of the drug but based on safety data that exists to support the intended route(s) of administration and intended use level(s).

Currently the only mechanisms that exist for excipient manufacturers to present excipient-specific information to the agency independent of a drug application are Type IV (Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation) or Type V (FDA Accepted Reference Information) drug master files (DMFs). However, DMFs are only intended to be reviewed by the agency in conjunction with a specific drug application and there is no consistent approach to DMF reviews. This may result in refuse to receive notifications (for novel excipients that are not really new chemical entities) or application delays.


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FDA toxicologists have referred IPEC-Americas to the Biomarker Qualification Program (BQP) as a possible model process for new excipients. IPEC-Americas believes that there are many important, relevant concepts in the program that, with modification, could provide a foundation for engaging FDA on modernizing a process for novel excipient safety review.

IPEC-Americas has offered to collaborate with FDA to define what the Agency would need to review in such a process. Information required for an excipient review could be similar to the type of information currently required for a Type II DMF for Active Pharmaceutical Ingredient (API) completeness assessment but with added focus on excipient safety.

There would also need to be development and implementation of a unique type of user fee system (different from the existing PDUFA user fee model) to fund FDA resources to perform independent safety assessments / qualifications of excipients.

IPEC-Americas has invited the FDA to continue discussions on possible approaches to create an improved pathway for review and acceptance of novel excipients based on defined criteria and mechanisms by which such a process could be formally recognized.

process would entail and implementing it.

IID Upgrade to Family Approach Also Urged by IPEC

Along with the explanation of the need for a more viable regulatory pathway for novel excipients, the IPEC-Americas’ comment paper on the generic drug user fee reauthorization includes a second section proposing changes in the inactive ingredient database (IID) and policies regarding the referencing of families of related excipients in ANDAs.

IPEC-Americas and FDA’s Office of Generic Drug (OGD) IID Working Group have been working together since 2011 to improve the IID’s content and functionality (see IPQ “Monthly Update” Nov./Dec. 2013, pp. 16-27), which impact FDA’s novel excipient determinations and the clearance hurdles involved.

Helping the cooperative effort has been the extra resources available to OGD to support projects that meet the GDUFA goals of creating a more efficient review process.

The two main IPEC concerns that remain open, the comment paper points out, are that:

• “the current IID and the policies regarding use ofthe database are insufficient to support efficient drug development and approval,” and

• “FDA policies and guidance (i.e., Refuse to Receiveand Controlled Correspondance) related to the review of inactive ingredients (excipients) in ANDAs continue to create confusion and result in longer review times for generic drug applications.”

After reviewing the concerns with the current situation, the

comment paper goes on to describe in more detail what a family approach to assessing the safety of similar excipients would look like and the benefits it would offer.

After reviewing the concerns with the current situation, the comment paper goes on to describe in more detail what a family approach to assessing the safety of similar excipients would look like and the benefits it would offer.

Following the presentation at the GDUFA public hearing and its submission of written comments, representatives of IPEC-Americas met wi th FDA toxicology experts from both the generic and new drug side at the end of July in pursuit of a decision from the agency on the acceptability of the family approach.

The meeting provided an opportunity for the IPEC representatives to explore its proposal in more detail. With the oral and written GDUFA comments also in hand, the association is hopeful that FDA can reach a favorable decision by the end of the year.

Other Global Excipient Database Efforts In Play

IPEC has also been engaged alongside FDA on other significant information management initiatives intended to help industry and regulators communicate about pharmaceutical excipients on a more global level and fill accuracy and content gaps in existing regulatory database efforts, such as the IID (see IPQ “Monthly Update” Jan./Feb. 2015, pp. 33-44).

• The projects include: A “Global Ingredient ArchiveSystem” (GInAS), being developed with broad international participation that would identify, organize, and catalogue all pharmaceutical ingredients in line with ISO standard 11238 on the identification of

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

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

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

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IPEC on the Family Approach to Assessing Excipient Safety

The following is a description in IPEC-America’s GDUFA comments of the current situation and why a family approach to assessing excipient safety is justified as a means of making the ANDA review processmore efficient and helping FDA and industry meet GDUFA timelines

Members of IPEC-Americas understand that many excipients are part of an excipient family of similar products and the different grades that exist within these families of excipients have no impact on the safety of the material. IPEC-Americas believe that in these cases, the use of a generic listing for the excipient family in the IID which lists the highest level of use in a particular route of administration should be appropriate to determine precedence of use levels that support the safety of the excipient for a given application of any excipients in the family.

The situation for many common excipients (e.g. hydromelloses, polyethylene oxide, dimethicones and carbomers) includes:

• Original safety data generated many years ago for “families” of products would require the same data to besubmitted for each grade of material, multiple times to different reviewers.

• Ingredients safely used often for decades without adverse “safety” events

• Risk of adverse event due to “safety” issues/concerns are relatively low

• FDA currently uses this approach for food additives and cosmetic ingredients and in the past has used it for pharmaceutical excipients

The current practice of requiring toxicology data for every grade of an inactive ingredient is not substantiated by scientific rationale. This is not aligned with a risk-based approach and does not provide for the best utilization of FDA resources. It does not add value or reduce risk due to safety of an ingredient.

medicinal products (IDMP)

• A “spectral library,” with USP participation, aimed atcreating a more coherent approach for authentication of materials, including APIs, glass, poisons, packaging materials, and excipients. The library will contain “fingerprint” spectra of confirmed materials that can

be used for comparison with pharma company testing results (ibid), and

• An “Excipients Knowledge Base,” spearheaded bythe academic consortium, the National Institute for Pharmaceutical Technology and Education (NIPTE), that is focused on cataloguing and comparing excipient properties.

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BMS’ Ricardo Zayas on Pharma Manufacturing and its Relationship with Excipient Suppliers

Two topics we will be discussing today: ● the first is a general topic regarding the general state of the pharmaceutical industry, past, present, and future ● and then we will switch over to more specific things related to excipients. I have divided [the latter] into two areas: ● some specific examples on the uses of excipients in the pharmaceutical industry ● and then what kind of things we can do in terms of partnership and collaboration so we can really maximize the value of our relationships.

I have divided [the latter] into two areas: ● some specific examples on the uses of excipients in the pharmaceutical industry ● and then what kind of things we can do in terms of partnership and collaboration so we can really maximize the value of our relationships.

Pharma – Past, Present and Future

Three areas that we will break the pharmaceutical industry down into: ● the 1970s and 1980s, which were very similar – those were years when the pharmaceutical industry was very stagnant ● the 1990s, where change started to occur, and ● the 2000s, which is basically where we are now.

The Past

The ‘�0s and ‘�0s characterized the pharmaceutical industry as very vertically integrated, where companies made everything from their own API to the bottles that they used to package the product that went to the US markets. It was vertical integration – that was a theme in the ‘70s and ‘80s. Globally fragmented – every country, every region basically did their own thing.

Just to give you an example: In 1998, I went on a one year developmental assignment with Warner Lambert to Germany. And a product we used to make for the US market here in Puerto Rico – it was four strengths and maybe 16 SKUs – in Germany, because it serviced a lot of countries, there was about 50 formulas and 250 or 260 SKUs. So that proliferation of SKUs really didn’t allow for an optimization of the manufacturing cycle and the supply chain.

That was a theme back then – higher costs because of that, lower harmonization, and stable supply. There weren’t a lot of things going on that really affected the supply chain. You pretty much made the product that was sold.

The 1��0s saw the emergence of generics and biotech. A lot of industry, a lot of different kinds of technologies, and the first wave of mergers and acquisitions and consolidation occurred.

Does anybody have any idea of how many pharmaceutical plants have closed here in Puerto Rico in the last fifteen years? About 27 plants was the last count. If you take a look at the kind of payroll that came out of each one of those plants, it is a huge blow to the local economy.

Does anyone know what the biggest contributor to that is? It is consolidation. A company has 50 plants. They buy another company with 50 plants. Pharmaceutical plants typically operate at about 60-70% utilization rates. Typically 50 plus 50 doesn’t equal 100 in this case. You have a huge level of sub-optimization. So 50 plus 50 is probably going to equal 70-80. So the biggest contributor of pharmaceutical plant closures over the last 15-20 years has been this right here – M&A and consolidation.

Major IT investment: everything from SAP to paperless plants.

Global quality standards rollout: We don’t have ten different sets of standards, right? Most companies really aspire

At the April IPEC/ExcipientFest conference in Puerto Rico in late April, BMS Pharmaceutical Operations Senior VP Ricardo Zayas gave a compelling presentation on the past, present and future of pharmaceutical manufacturing and the increasingly difficult role that excipients and the relationship with excipient suppli-ers will play in the success of new pharmaceutical products.




to having one single set of quality standards around the world.

The Present

In 2000, operators were in focus. I worked with two companies, both of which were involved in serious consent decrees. I joined both companies to help them get out of that, because I had experience. When I joined Warner Lambert, they brought in a whole new management team.

There were a lot of things that contributed to that – this is not anything confidential; there are a lot of writings around this. The single most important contributor was a cost-cutting mentality – for lack of a better descriptor, a slash-and-burn kind of mentality – that really took them a place where they didn’t want to be. It turned out costing billions of dollars for the companies – both Warner Lambert and Schering Plough – which both in the end were purchased by other companies. So a very serious thing here.

Operational focus: What it does is that it really makes you more competitive, but it does it in the right way through deep seated analysis of your operations and ways to get better in your operations.

Global supply strategies: You really want a global strategy for a product that is going to sell $3 billion around the world. And by doing that you can maximize that product and make that a $4 billion dollar product. But you really want a global strategy for your top products.

More M&A and consolidation: Health authority expectations continue to increase globally. There is more and more harmonization. People complain, we complain about the fact that health authorities around the world aren’t completely harmonized. That’s true, they are not completely harmonized, but they are a lot more harmonized than they were 15 or 20 years ago.

Outsourcing: Many companies are now seeing outsourcing as a tool or the way to get rid of products of a very low volume or very low in terms of profitability. We are looking at outsourcing with completely different needs. We have set up an external manufacturing organization that is very very sophisticated and that is well staffed and has the right people to do this. Because it is not necessarily about manufacturing. When you go into external manufacturing in a very committed way, you do it knowing that you have to manage companies that don’t report to you. It is more about managing relationships than it is about knowing manufacturing.

The Future

New levels of cooperation and clear product differentiation: This is very important as we go forward. If you have been reading about what is going on in R&D in the pharmaceutical industry in the last three or four years or five years, there are a lot of very very innovative products out there. There are products that can cure certain types of Hep C. There are products that in four or five years could be on the verge of curing HIV – a lot of innovative products.

I think the pharmaceutical industry, unjustly in many ways, has been accused over the last ten or twenty years of focusing more on the symptoms rather than the disease. I think there is a big focus on the disease now and we are going to see this wave in the next 10-20 years. I think that a lot of the diseases and ailments that really hurt us now around the world are going to disappear in the next ten or 20 years.

Some of the key metrics that govern anybody that has been in a pharmaceutical manufacturing facility or the pharmaceutical manufacturing world: These are measures that are pretty globally in nature – overall equipment effectiveness, annual productivity, first/pass yield, lead time in days, and inventory of finished goods in days.

The pharmaceutical industry has typically not been great at utilizing their assets. If you are going to build a pharmaceutical plant from scratch now, it is probably going to cost you $600-700 million. I was impressed until I visited Samson Biologics last week in Korea, and we got a tour of their electronics facility – one of their wafer manufacturing facilities. Each one cost $10 billion to build. So that was very humbling to say the least.


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If you take a look at how the pharmaceutical industry compares with automotive, aerospace, computer, and consumer goods, take a look at this: Overall equipment effectiveness, 10-60%. What this means is that if we buy a packaging line that is probably built, installed, and qualified and cost $10 million, we typically use it at a rate of 10-60% – an average of about 35% utilization. So if you had your own operation, would you be happy with a 35% utilization? Absolutely not. So we lag behind these.

If you take a look at the other measures of productivity and improvement, we lag behind almost all of these industries here.

Pharmaceutical industry five-year outlook: These are some of the predictions.

• By 2018, global sales will be about $895 billion. This is at a 3.8% compounded annual growth rate. 2012 did see an unprecedented sales decline of 1.6%. Pharmaceutical sales had never declined until 2012, just two and a half years ago.

• $230 billion in sales at risk between 2013 and 2018. This is loss of exclusivity, patent expiration.

• R&D spend is forecast to be about $150 billion in 2018. This again is at a compounded annual growth rate of 1.4%.

• Hepatitis C and the immuno-oncology pipelines are the ones that are deemed to have the highest value….

• By 2018, three years from now, biologics will be about 50% of the top 100 sales. This is really amazing. If we take a look at where biologics was a while ago, and to say, even dream, that three years from now, it will be about 50% of top 100 sales – this is a significant change.

So the industry is facing significant dynamics:

If we take if from the top, emerging markets: Brazil, India, China….

Cost and access: It is not anymore about having the best product in the world, [because] if government or if private payers are not willing to pay for it, you might as well not have a great product…. You need access in different countries.

Supply chain integrity: Anyone want to try and guess how much product is lost every year to either theft or copycat products? Depending on who you ask, it could be up to $70 billion – copycat products, fakes, thefts. It is amazing. It is a huge industry of ‘legal’ drugs….

Demand drivers – business interruptions: More and more you see every day the boards of companies really demanding from their management to have back ups across the board for all their products.

I was just having a conversation with some of the members of the team here in Puerto Rico at BMS. One of our big products, Eliquis, we need to double up on all the excipients that we use for the product. It is a big product and it is going to be an even bigger product, so we need to protect it.

Evolving portfolios: If you take a look at the past, I think in our cases, BMS, the Plavixes of the world, the Lipitors of the world, where you would make 5 or 10 billion tablets in a direct compression formulation. Oh boy, those were the good old days [where] you mix it, and you compress it.

Well, not anymore. We are talking about very very targeted products for very very targeted diseases. If you take a look at our portfolio in Bristol-Myers, we are in immunoncology, virology, cardiology, degenerative diseases such as Parkinson’s and Alzheimer’s. These are very complex products with very complex formulations – small volume products, very profitable products, to meet unmet needs. It is significant.

In the past there was direct compression. In the future it is going to be peptides, oligonucleotides, antibody-drug conjugates, where you actually mix the world of cytotoxic drugs, very potent compounds – you put them on a protein,




and the protein acts like a warhead. You have a very potent compound going to a very targeted area in the body. You have to make those separately and then you have to conjugate them. You need to figure out how to put them together. So there are very complex processes, very complex chemistry involved in the future. It is not an easy thing. [You need] technology, obviously, to support that.

This is really interesting: A typical product is going to cost about $1.3 billion to take to the commercial space to get a market authorization for approval. One out of 5,000 compounds will reach clinical trials. And one out of five compounds that reach clinical trials are going to obtain a market authorization and you can actually sell. So if you do some quick math here it is like one out of every 25,000 compounds is going to receive a marketing authorization…. So the probability of a compound actually repaying the investment in R&D is like .04%. That is amazing. And at a cost of $1.3 billion per product – that pretty much gives you the idea of how it works.

Implications for the pharmaceutical supply chain: increasing complexity; supply chain security as I have mentioned; loss of exclusivity; and capacity utilization.

A lot of people like to work in the consumer products industry because it is very stable. Advil is a bad example because

Advil got a huge jump after Tylenol had their issues. Advil was selling 4 or 5 billion tablets for a number of years. It is pretty stable. You work in a facility like that, it will pretty much grow at 3-5% per year. It is not going to be $10 billion in sales, but it is not going to fall off a cliff either. It is something that we have got to deal with here.

Geographic presence: Some markets require you to be there. In Brazil you have to have a presence. Argentina you have to have a presence – Saudi Arabia, Russia. We are now looking at a Hep-C opportunity in Russia that will require that we do more in that country. What that more is going to look like we haven’t figure out yet, but we need to do more in Russia. It is the nature of today’s pharmaceutical world.

Regulatory expectations are getting tighter and tighter. 20 years ago, a lot of regulators were focused on end results. Now they focus on the drivers of the drivers of end results. So they go way back into your processes.

Emergence and adoption of new technologies: I already mentioned that.

Energy and sustainability: We have to be good corporate citizens. It is the right thing to do.

People and talent management: you can’t do any of this if you don’t have this.

So as Marshall Goldsmith said in his book, ‘what got you here wont get you there.’ So this is the general state of the pharmaceutical industry….

How Excipients Can Help

Now we will go into specifics of how excipients can actually help. If you take a look at this you will notice I have divided this into two areas. The role of excipients and partnerships in enhancing competitive edge. Three key phrases: Role of excipients, partnerships, and enhancing competitive advantage.

Two areas that I divided this into: ● excipients enabling drug products for patient needs, and ● excipient vendors and DP manufacturer partnerships….

Specialty Excipients

Let us take a look at this – specialty excipients: This is interesting – cyclodextrin-enabled intramuscular product. This is one of our products. If we wouldn’t have done this, the product probably would have never made it to market.

The solubility challenges in the product: Poor free-grade solubility. Solubility improved by more than 200,000 fold by a combination of Captosol and the right pH. This is not a plug for Captosol…. It just happened to be the cyclodextrin base that we used for this particular formulation. From an insoluble free drug, add free cyclodextrin, and out came a


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soluble cyclodextrin complex. If we wouldn’t have done this, there wouldn’t have been a drug. This is a great example of what has been done with a specialty excipient….

New Uses of Old Excipients

The new uses of old excipients for current needs: This one is really interesting. This is something that I borrowed from our R&D colleagues. They like to say, ‘it is not high technology, not low technology, but just the right technology.’ This is what they mean by this….

First of all, one of the uses of an ‘old excipient’ – PVP-enabled product. Again, this is one of our products. These are the characteristics of the product. It is a high potency API, low-dose strength – .5 milligram and 1 milligram tablets.

Obviously, content uniformity is a challenge with these low doses. Handling is also a challenge from an EHS perspective, because it is a very potent compound.

Wet granulation using micronized API was an option. But then we find out that PVP, a binder (this is povidone – it has been used in the pharmaceutical industry for years as a binder in wet granulations) could actually solubilize this product. So all of a sudden PVP comes to the rescue here and turns this into a product.

Again, the addition of the dissolved drug in PVP solutions or in wet granulations offers several advantages: The first advantage is that no micronization of API is needed and reduces the fine powders in handling. This was a big advantage for us. It eliminates a complete step. It delivers the drug uniformly, and as you as all know for a very low dose compound, this is very very important. It did not affect the drug polymorph in the drug product. In other words, the dissolution of the API in the PVP and the subsequent recrystallization after granulation basically yielded the same API characteristics as the input API. This is very important.

Innovative Technologies

So, innovative technologies: I gave one example of a specialty excipient, one example of a new use for an older excipient, and I would like to give a two or three examples of innovative technologies using excipients….

Lets talk about this one for a minute – amorphous solid dispersions, ASDs. This is a key phrase here, and for you folks, I think this is probably the more interesting thing on this slide: A significant amount of the drugs that are in Phase 1/Phase 2 development are water insoluble and need drug delivery technologies. ASDs are just one of them. There are others: There are nanotechnologies. There are lipid formulations. There are a lot of different technologies that you can use. But this is one of them.

Amorphous forms of API enhance solubility, but are often unstable on their own…. When you have a drug that is insoluble, you are going to have dissolution issues. An amorphous form of the API enhances solubility, but it is often unstable. They typically have poor stability profiles on their own.

Along comes ASD to the rescue. Amorphous solid dispersion technology overcomes this challenge. Some of these are spray drying, hot melt extrusion – you might be familiar with these. Layering in a fluid bed dryer is another one. There are about a half-dozen examples of these we could use. This is very important here – ASDs are molecular dispersions of amorphous drugs in polymers and other excipients such as surfactants and stabilizers.

If we take a look at this, there are several products that are already in the market using these technologies. We have several in development – numerous compounds in pre-clinical and clinical development and technology enabled by excipients.

This is an important slide. Even though, in the end what you want is an amorphous solid dispersion – it is a combination of the API, the polymer that you decide to use, and other excipients under a given process – the key point here is that this is enabled by the polymer. Without the polymer, it couldn’t happen. This is what we are discovering. It couldn’t happen without the polymer, and then the amorphous characteristics of the API would basically disappear. So it is a very specific technology that is enabled by these polymers here, and this is obviously your area of expertise.




This one is really interesting: This is a controlled release injectable product. What we are looking at here is these are release modifying excipient properties controlling the microsphere technology performance. What do I mean by these?

This cartridge here happens to be an injectable cartridge for a diabetes drug. The interesting thing about this is that it slowly releases medicine all week long. If you have got diabetes, can you imagine what this means? So this is a microsphere. It is the entire sphere here. It has got small particles of the medicine, but by using these specific excipients you can really control the dissolution of this microsphere. It basically dissolves over a one-week period, and you get a uniform dose over seven days because you are using this technology – very interesting.

This is one of my favorites: lipid liquid crystals for sustained subcutaneous release delivery. Very interesting. This is Camurus’ fluid crystals, the injection depot. Camurus is a Swedish biotechnology firm. They have been around for about 25 or 30 years. They focus on manufacturing nano drug delivery systems.

If you take a look at this, this one is very interesting. You combine the drug with a mixture of long chain lipids, and it turns out to be a low viscosity solution. The formulation when injected forms a liquid crystal resulting in a depot of sustained release.

You inject this subcutaneously. It forms this depot and interacts with water in your body…and then you get the dispersion of the ingredient coming out. The great thing about this is that the release profile can really be modified by using various lipids in combinations. It could be over 24 hours, 48 hours, 5 days. You can control it. Obviously there are requirements, but you can pretty much control this.

What is the obvious advantage of this? Would you rather take a drug three times a day or three times a week?

What does this mean as a level of importance for pharmaceutical manufacturers? It creates differentiation. We are at a point where you take a look at the product portfolios in most of the pharmaceutical industry – even the ones we are in, immuno-oncology – if you have been reading the news, it is a footrace between Bristol Myers, Merck, AstraZeneca, Roche. When you are competing with companies that are absolutely huge – we are a $16 billion company; Roche’s oncology business alone is $25-30 billion; these are monsters – so you have got to create differentiation.

A lot of these products start to look alike. The Hep C area, which is one we are in – we compete head-to-head with AbbVie and Gilead. You have got to create some sort of differentiation. This creates differentiation for your product. So it improves compliance. It creates differentiation. It allows you to manage your lifecycle of the product better because you have options with the product depending on the markets you are going into – very interesting technology.

The Excipient Vendor/User Partnership

This is a very important slide for you, because this is what we are looking for from all of you: excipient vendor and user partnership customer-focused innovation. This is a very long title for saying that we want to work together.

I will talk about these three examples. There are a lot more…. Several new grades and forms of excipients have been introduced – completely new. That is great. But for us it creates a more difficult regulatory pathway. So maybe a compromise, an alternate, could be not a completely new excipient but a variation with a distinct functionality and purpose. Maybe that is something that is already a compendial excipient, with a specific functionality. Maybe that is the compromise.

This is an example: low peroxide polymer excipients for stability and shelf life of oxidation-sensitive products. This is an actual example that we have in our company. It was a compromise – not completely new. Tweaking a bit the ones we were working with already, we came up with a very good solution for us.

Co-processed excipients: We get this. They are designed for multi-functionality – [for example,] solicified microcrystalline cellulose. We get that. But on the other hand, our point of view is that is has got to have a distinct advantage over physical mixtures, because we might be able to mix these internally. From end-user that is not always the case.


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Our message to you is to listen to us. We might be able to come up with something that has a specific purpose, a specific functionality, and we might not necessarily want a laundry list of excipients. We might want one, two, or three that are very specific to what we need. So if we can work together and you are willing to listen, we might come up with something really great. That is the message here.

Over here, I am going to do a 180 on this. Because what I said here is that ‘don’t necessarily give us a novel excipients because they have complex regulatory pathway. Because the regulators don’t understand them very well, it is harder to get approval.’ But I am saying here the exact opposite. As always, the more difficult road is the one that could be most beneficial for patients and the most profitable for companies.

Novel, chemically distinct excipients are limited. Again, the complex regulatory path in the US is a significant barrier. That is true. But if you get approval there is huge upside – huge benefits to the patients that need these products.

The potential for a significant competitive advantage: Again, the example that I gave a while ago was Captosol. So again, here sometimes we need to compromise on not necessarily new excipients, but maybe meet somewhere in the middle of the road with something more specific. These here, co-processed excipients, they really should have from our perspective a distinct advantage over our own mixtures. We should take a look at [novel excipients] even if the regulatory pathway is more difficult.

Excipients serving a competitive advantage – managing excipient variability during the product lifecycle: Product robustness and reliability is dependent on excipient variability management.

I will mention the four or five bullets, and then I will talk about what I really mean behind all of this and the business implications of all of this:

• understand the product

• understand the excipients – this is motherhood and apple pie, but it doesn’t always happen

• carry out wholistic, realistic risk-based assessments of the interactions between APIs and excipients as well asmaterial properties and process outcomes

• work with excipient suppliers to get access to a wide range of historical data

• supplement, if necessary, with additional robust tests

• more open discussions on supply chain reliability.

Every time I do a conference like this, I always get asked the same question, either in public or in private: ‘What is the single most important thing that I look for in a pharmaceutical manufacturing facility?’ I always answer it the same way: ‘Reliability: Tell me you can do five things and do them extremely well rather than telling me that you can do 20 and do them at 50%.’ Reliability is the single most important thing.

Which is the single most important metric that I look at in any of the plants that I have ever managed? It is right first time.

Behind almost everything that happens wrong in a pharmaceutical manufacturing facility, there is a quality investigation, deviation, whatever you want to call it – different companies call it different things. There is an inherent variability in the process that causes the deviation, causes investigations. And these investigations lead to what? All the re’s: rejects, reworks, reprocessing, retesting, re-inspections, repackaging.

If you talk to any executive in pharmaceutical manufacturing, they will tell you that the cost of poor quality always has an investigation behind it. If you add to all the re’s, the lost revenue that comes out of backorders – because almost every back order in the pharmaceutical industry is due to an investigation or process variability – it is easily in the $100s of millions, which is translated into many points of earnings per share.




This product robustness and reliability to me is all about controlling variability in your processes. And a big enabler to controlling variability in your processes is [communicating with] our excipient suppliers. It is very important that we start speaking the same language because you are going to see more of this.

When I first joined Bristol three years ago, I asked why we are doing this product robustness, and they told me it was a regulatory requirement. Wrong answer. It is a regulatory requirement, but that is not the only reason you do it.

A regulatory requirement is a minimal expectation. Nobody comes to work inspired every day to say, well, today, I am going to comply. Not very inspiring. You come to be the best. You come to be the benchmark in what you do. You want to be the best in the industry. You don’t come to comply. We come to do that also, of course, but it is not very inspiring. And it is not going to give you a leg up on your competition. It is not.

This will. You get CPKs that are way up there. Now the interaction between the API and the excipients is vital in this. You improve that, you reduce the number of investigations, you reduce the number of OOS’s, you reduce your backorders, and maybe more importantly you protect those billion dollar drugs. Because all it takes is one failure in one ingredient to backorder and maybe have to recall a two, three, four or five billion dollar product in major markets. That is all it takes.

Pharmaceutical manufacturing is very very complex. You put hundreds of materials, hundreds of people, hundreds of pieces of equipment and instruments under one roof, and have them work for 24 hours a day. On any given day, 10, 20, 30 thousand things can go wrong. Our job is to make sure that nothing goes wrong, and this goes a long way towards doing that. It is very important, and you folks should be playing a major roll in that with our late stage development.

Clearly, sustainability, a competitive advantage, requires a partnership between excipient vendors and end users. And we want to partner, and you are going to see more of this. You are going to see more and more that manufacturing groups are going to work more in concert with late-stage drug development to really develop drug products that are sustainable and robust. You folks play a very important role in that, but it is important that you start speaking this language.

The development to launch speed is our single most important imperative right now at BMS.

You might have heard a while ago that we are in a bit of a horse race with Merck in terms of our IIO compounds. It is not any different with any other compounds. This is not the industry that it was 20 years ago. Two or three months could make a difference between a nice drug or a $2 billion drug. So this is very very important. So we need to work together now more than ever at reducing this. It is not whether we can launch a product…..

I will give you an example: Sovaldi. It is a hepatitis C drug produced by Gilead. Do you know how much it sold its first year, last year? Close to $10 billion. That is why Gilead’s shares are where they are. I have a friend that works for Gilead. He is always smiling. He is a very happy guy.

Do you know why they were able to launch Sovaldi ahead of everybody else? Because they cut their first in human, their FIH, to launch cycle time from typical hepatitis C seven years to three years. A lot of that was risk management. But a lot of it was good formulation work.

I know you guys get this, but it is important that you internalize this, because this is the future. This is where we are headed. Development to launch is going to be the single most important differentiator going forward. It is very important. And our work with you folks is very important to be able to get us there.

Summary

In summary, historically excipients have been considered as inert materials with some functionality in dosage forms. ‘Oh yeah, it is the stuff that we mix with our API to bind and to allow it to flow and all that good stuff.’ Not anymore. The criticality of excipients in drug product quality, processability and stability is growing – or the recognition of criticality

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has been growing. I think it has always been critical, we just hadn’t really recognized it as an industry.

Complexity and drug candidate properties and drug product target profiles call for new excipient technology and paradigms. I gave five examples of novel uses.

Quality-by-design and other regulatory expectations have increased focus on excipient understanding. We were just having a conversation now. Okay, a very important product got a submission with lactose. We need to qualify another supplier. Is it PAT enabled? Is it not PAT enabled? We have these conversations all the time.

Managing excipient variability through product supply requires greater partnership between excipient vendor and end user.

If you have these five takeaways, it is important. But my single most important take away to all of you is that, if we want to develop a real successful partnership for both parties, we need to start speaking both languages – us, your language, and you our language, and you need understand what kinds of things are important for us.

I have tried to highlight over the last 40, 45 minutes, very quickly, where the pharmaceutical industry is coming from, where it is headed, and the significant role that excipients can play in the pharmaceutical industry. They are not inert materials with some functionality. They are enablers of product success. They are enablers of a person somewhere in the world being actually able to use a product that can help them with their terrible disease or not be able to use it.

IPQ wishes to thank the following sponsors:

For subscription and sponsorship information visit IPQpubs.comor contact Wayne Rhodes — [email protected], Tel: �0�-��1-��0.

http://www.ispe.org/

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http://www.westpharma.com/

http://www.casss.org/

http://www.parexel.com/

http://www.ipecamericas.org/

http://www.rx-360.org/

http://www.dba-global.com/usa

http://www.edqm.eu/

http://www.pda.org/

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GMP Conference 4 - 5 November 2015

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Hélène BrugueraEDQM, France

Yong Seok KoNIFDS, South Korea

Anabela MarcalHead of Compliance and Inspection Department EMA, United Kingdom

Mieke van der MeulenSenior Inspector, Dutch Healthcare Inspectorate, The Netherlands

Ewan NortonMHRA, United Kingdom

Jean-Louis RobertChairman of the EMA QWP, United Kingdom

Alex ViehmannCDER, US FDA

Toru YamaguchiPMDA, Japan

Wiebke BähkerMerck, Germany

Denis ComeyneJanssen Pharmaceutica, Belgium

Marieke van DalenAspen Oss B.V., The Netherlands

Uwe FischbeckMerck, Germany

Betsy FritschelJohnson & Johnson, USA

Koen NauwelaertsEuropean Generic Medicines Association, Belgium

Luisa PauloHovione, Portugal

Janeen Skutnik-WilkinsonBiogen, USA

Anthony StoreyPfizer, United Kingdom

Francois VandeweyerJanssen Pharmaceutica, Belgium

Hilde VannesteJanssen Pharmaceutica, Belgium

Lore VignoliRoquette Freres, France

Victoria WaddingtonMacfarlan Smith Limited A Johnson Matthey Company, United Kingdom

Tim WatsonPfizer, USA

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Updates in Brief

CMC/REVIEWDraft Guidance on Dissolution Testing

In early August, FDA issued a draft guidance on “Dissolution Testing and Specification Criteria for Immediate-Release Solid Oral Dosage Forms Containing Biopharmaceutics Classification System Class 1 and 3 Drugs.” The draft guidance was developed to provide manufacturers with recommendations for submission of new and abbreviated new drug applications (NDA and ANDAs) and investigational new drug applications (INDs) for immediate-release (IR) tablets and capsules that contain highly soluble drug substances. It describes when a standard release test and criteria may be used in lieu of extensive method development and specification-setting exercises. Comments are due by October 2, 2015. When final, this guidance will supersede the guidance for industry on “Dissolution Testing of Immediate Release Solid Oral Dosage Forms,” which was issued in August 1997 for Biopharmaceutics Classification System (BCS) Class 1 and 3 drug substances in immediate-release drug products that meet the criteria in the guidance. For class 2 and 4 drug substances, applicants should still refer to the August 1997 guidance.

Analytical Procedure and Method Validation Guidance

In late July, FDA released a final guidance on “Analytical Procedures and Methods Validation for Drugs and Biologics.” FDA had issued a draft of the guidance in February 2014. The guidance updates the draft guidance FDA put out in 2000, which, in turn, was an update of its 1987 guidance on “Submitting Samples and Analytical Data for Methods Validation.” The 2015 guidance discusses how to submit analytical procedures and methods validation data to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products. The guidance applies to new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), and their supplements, but not to investigational new drug applications (INDs). Changes from the 2014 draft include clarifications regarding: ● appropriate reference standards and materials ● analytical method validation ● verification protocols, and ● differing expectations for methods referenced in BLAs.

Injectable Drug Allowable Excess Guidance

In late June, FDA released a final guidance on “Allowable Excess Volume and Labelled Vial Fill Size in Injectable Drug and Biological Products.” The guidance covers drugs in ampules or vials that are intended for injection, and does not cover prefilled syringes or intravenous infusion bags. The agency notes in the guidance that injectable vial misuse, including unsafe handling and injection techniques, “has led to vial contamination and an increased risk of blood-borne illness transmission between patients.” Inappropriate excess volume and labeled vial fill sizes, it maintains, are two factors that may contribute to unsafe handling and injection practices by consumers and health care providers. It points out that even when appropriately labeled, single-dose vials that contain significantly more drug than is required for a single dose may result in the misuse of the leftover drug product. The guidance clarifies the agency’s position on vial overfilling and makes recommendations on vial fill levels based on the product type and intended use. The draft was released in March 2014, and no comments were submitted to the agency.

PDUFA VI Public Hearing

In mid-July, FDA held a public hearing for input on the sixth iteration of the Prescription Drug User Fee Act (PDUFA VI). The meeting began with opening remarks from FDA’s Acting Commissioner Stephen Ostroff. Afterward, various stakeholders, in-cluding the Pew Charitable Trusts, National Organization for Rare Disorders (NORD), the Pharmaceutical Research and Manu-facturers of America (PhRMA), the Biotech Industry Organization (BIO) and the Alliance for Regenerative Medicine (ARM), pre-sented their views on PDUFA, including responses to the following questions posed by the agency prior to the meeting: ● “What is your assessment of the overall performance of PDUFA V thus far?” ● “What current features of PDUFA should be reduced or discontinued to ensure the continued efficiency and effectiveness of the human drug review process?” ● “What new features should FDA consider adding to the program to enhance the efficiency and effectiveness of the human drug review process?” [For a review of the IPEC-Americas comments on PDUFA advocating for an excipient safety review pathway, see the story on pp. 28-43.]

UNITED STATES

http://rx-360.org/Portals/1/Guidance/FDA Tablet Solubility/DG FDA-1997-D-0187.pdf

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM386366.pdf

http://igmpiindia.org/Fiilng final guideline.PDF

http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm117890.htm

http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm117890.htm


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GDUFA Drug Approval

In a press release in mid-August, Spear Dermatology Products announced FDA approval of Tretinoin Gel, a generic version of Valeant’s Atralin, as the first abbreviated new drug application (ANDA) approved under the Generic Drug User Fee Act (GDUFA) 15-month approval clock in FY 2015. The application was approved in only ten months. FDA has cited the approval as an example of how good communication and a complete application that does not require multiple follow-ups can allow for fast approvals under GDUFA.

CVM CMC Two-Phased Submissions

In late August, FDA released a guidance, “Two-Phased Chemistry, Manufacturing, and Controls (CMC) Technical Sections” – finalizing an October 2014 draft – which provides recommendations to sponsors submitting CMC data submissions to CVMto support approval of a new animal drug or abbreviated new animal drug. The two-phased process allows for two separate CMC submissions, each with its own review clock, and each including complete appropriate CMC information that is available for review at the time of submission. The guidance specifies the technical details of how the process works, the review clocks, the information that is appropriate for each technical section submission, and the possible review outcomes. The guidance also includes CVM’s recommendations for meetings between the Division of Manufacturing Technologies and the sponsor during this process to ensure concurrence with the approach used for the CMC technical section.

First 3D Printed Drug Approved

In early August, FDA approved Aprecia Pharma’s Spritam, an oral solid drug formulation of the epilepsy drug levetiracetam, manufactured using 3D printing technology, and used for the treatment of epilepsy seizures. Aprecia’s proprietary 3D printing process, “ZipDose,” produces pills that are more porous than those made by conventional tableting processes, which dissolve almost instantaneously when added to liquid. Aprecia refers to these new 3D-printed pills as “fast-melt,” to differentiate them from tablets and capsules. FDA approval of the 3D printing process could pave the way for individualized medicine applications.

Register

2015 ISPE Annual Meeting8 – 11 November 2015Philadelphia Marriott DowntownPhiladelphia, Pennsylvania USA

http://www.spearpharma.com/approval-of-first-generic-for-atralin-tretinoin-gel-0-05/

http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-av-gen/documents/document/ucm419043.pdf

https://www.aprecia.com/pdf/2015_08_03_Spritam_FDA_Approval_Press_Release.pdf

http://www.ispe.org/2015-Annual-Meeting




Outsourcing Facility Guidance

In mid-August, FDA announced the availability of a final “Guidance for Entities Considering Whether to Register as Outsourcing Facilities under Section 503B of the Federal Food, Drug, and Cosmetic Act.” The guidance addresses the regulatory implications of registration as an outsourcing facility under the Drug Quality and Security Act (DQSA). The final guidance was issued as a draft for comment in February 2015, and minor changes were made based on comments from 11 stakeholders. Firms applying for outsourcing status have been included in the wave warning letters that have flowed from FDA’s inspection blitz of injectable compounders which began in 2013 (see IPQ “Monthly Update” March/April 2014, pp. 36-39).

Rare Disease Development Support

In mid-August, FDA issued a draft guidance on “Rare Diseases: Common Issues in Drug Development.” The draft aims to assist sponsors of drug and biological products for treating rare diseases in conducting more efficient and successful development pro-grams. In addition to an introduction, background and reference sections, the 19-page guidance includes sections on: ● natural history studies ● disease pathophysiology and identification and use of biomarkers ● nonclinical studies ● efficacy endpoints ● evidence of effectiveness and safety, and ● chemistry, manufacturing, and controls (CMC). Comments are due by October 16. FDA also announced the availability of grant funds for the support of development of a Natural History Database. The National Organization for Rare Disorders (NORD) is developing an Internet-based data collection tool with promise to further the accu-mulation of natural history data for many rare diseases. The goal of the grant is to enable NORD to further develop, refine, and disseminate the database tool.

Botanical Drug Draft Guidance

In mid-August, FDA announced the availability of a draft guidance for industry, “Botanical Drug Development” – a revision of a 2004 guidance. The general approach to botanical drug development has remained unchanged since the 2004 final guidance. However, based on improved understanding of botanical drugs and experience acquired in the reviews of NDAs and INDs for these drugs, specific recommendations have been modified and new sections have been added to better address late-phase de-velopment and NDA submission for botanical drugs. It provides recommendations regarding development plans for botanical drugs to be submitted in new drug applications (NDAs) and specific recommendations on submitting investigational new drug applications (INDs) in support of future NDA submissions for botanical drugs. In addition, it provides general information on the over-the-counter (OTC) drug monograph system for botanical drugs. Although this guidance does not intend to provide rec-ommendations specific to botanical drugs to be marketed under biologics license applications (BLAs), many scientific principles described in this guidance may also apply to these products. The comment period extends to October 16.

GMP/INSPECTION

FDA Drug Shortage Notification Regulation

A regulation proposed by FDA in 2013 requiring drug and biologics manufacturers to notify the agency in advance of impending drug shortages has been finalized and will take effect on September 8. The “Permanent Discontinuance or Interruption in Manufacturing of Certain Drug or Biological Products” regulation implements Title X of the 2012 FDA Safety and Innovation Act (FDASIA) (see IPQ “Monthly Update” October 2012, pp. 4-13, Jan./Feb. 2013, pp. 17-23, and March 2013, pp. 2-8). It requires manufacturers of drugs, biologics, and vaccines to notify FDA electronically six months prior to any event that would cause a meaningful disruption in the supply of a life-saving drug. If this is not possible, the regulation states, then companies must notify FDA within five business days of the event’s occurrence. Included with the Federal Register announcement of the final reg (link provided above) is a lengthy description of it and an explanation of FDA’s responses to all the significant comments that came in on the proposed rule. While no changes were made to the proposed rule as a result of the comments, the responses by the agency to them provides a wealth of additional insight into the rule’s intentions and interpretation. [For more on agency and industry drug shortage efforts, click here.]

https://www.federalregister.gov/articles/2015/08/12/2015-19740/guidance-for-entities-considering-whether-to-register-as-outsourcing-facilities-under-section-503b

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

http://www.ipqpubs.com/wp-content/uploads/2015/09/rare_disease_draft.pdf

https://www.federalregister.gov/articles/2015/08/17/2015-20130/disease-natural-history-database-development-u24

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM458484.pdf

https://www.federalregister.gov/articles/2015/07/08/2015-16659/permanent-discontinuance-or-interruption-in-manufacturing-of-certain-drug-or-biological-products

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

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

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

http://www.ipqpubs.com/?s=%22drug+shortage%22&submit.x=31&submit.y=6


JULY/AUGUST 2015 �� ......... ....


CPG on Product Tracing Requirements

On July 1, FDA issued a compliance policy guide (CPG) on product tracing requirements as part of its implementation of Title I of the 2013 Drug Supply Chain Security Act (DSCSA) (see IPQ “Monthly Update” January 2014, pp. 13-20). The guidance addresses the readiness of dispensers in the pharmaceutical distribution supply chain to comply with the DSCSA requirements related to product tracing, including the exchange of transaction information, transaction history, and transaction statements. For dispens-ers, the requirements went into effect on July 1, 2015. In the CPG, FDA notes that it does not intend to take action against dispens-ers who, prior to November 1: ● accept ownership of product without receiving product tracing information, prior to or at the time of a transaction, or ● do not capture and maintain the product tracing information. Also provided is further detail about the scope of the CPG and the agency’s expectations for dispensers and trading partners involved in transactions with dispensers.

Legionnaire’s Bacteria at GSK Plant

In early August, routine testing of water in a cooling tower at a GlaxoSmithKline (GSK) plant near Raleigh, North Carolina, revealed the presence of Legionella pneumophila – or Legionnaire’s bacteria – which can cause a fatal form of pneumonia. As a precaution, the plant was closed and nearly half of the 850 employees at the plant were asked to stay home until the cooling tower cleanup could be completed. The plant produces inhalation medicines, including Glaxo’s asthma product Advair, as well as other drugs for other pharma companies. The plant reopened six days later. Glaxo officials emphasized that there is no evi-dence that the bacteria infiltrated any medications and that the material in the cooling tower “does not come into contact with product manufactured at the facility.” An outbreak of Legionnaire’s disease in the Bronx section of New York City this summer that sickened more than 120 people and killed 12 was traced to a cooling tower at the Opera House Hotel, New York’s Channel 4 News reported in late August.

USP/USAID Secure Supply Chain

In late August, the US Pharmacopeial Convention (USP) announced that it is working with the United States Agency for Interna-tional Development (USAID) to secure health supply chain systems and ensure the safety of medicines as part of USAID’s Global Health Supply Chain (GHSC) Technical Assistance program. USP will set up and manage quality assurance (QA) systems, train QA staff, help suppliers apply standards and QA tools, help maintain product quality during distribution, and raise global aware-ness about threats to the supply chain.

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http://rx-360.org/Portals/1/Guidance/FDA DSCSA Serialization/FG DSCSA Dispensers Compliance Policy.pdf

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

http://www.nbcnewyork.com/news/local/Legionnaires-Disease-New-York-City-Bronx-Cooling-Tower-Death-Sick-Outbreak-Source-Health-Department-322407892.html

http://www.usp.org/news/usp-helps-partners-lower-and-middle-income-countries-safeguard-quality-medicines-through-national-and-regional-supply-chain


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PDA 10th Annual Global Conference on Pharmaceutical MicrobiologyInspiring innovation and exploring current trends and challenge to product quality and infection control in the global market

October 19-21, 2015 | Bethesda, MDBethesda North Marriott Hotel & Conference CenterExhibition: October 19-20 | Courses: October 22-23

PDA’s 10th Annual Global Conference on Pharmaceutical Microbiology will address pressing challenges to product quality and infection control in today’s global market including:

• Ebola: Exploring the True Science and Global Regulatory Effort

• Urban Myths• USP Updates

• The Next-Generation Sourcesof Antibiotics

• Regulatory Updates – What’s Going On within FDA and PIC/S?

• Ask the Regulators Panel Discussion• And Much More!

A distinguished line up of academic, industry and regulatory speakers is set to share industry experience, discuss current challenges and provide a platform for interaction and knowledge sharing between conference participants, augmented by an “audience response system.” Hear from:

• Luciana Borio, MD, Assistant Commissioner, Counterterrorism Policy and Acting Deputy Chief Scientist, Office of Counterterrorisand Emerging Threats, OC, FDA

• Reyes Candau-Chacon, PhD, Biologist,CDER, FDA

• Alan Dobson, PhD, Director,Environmental Research Institute andProfessor, Environmental Microbiology,University College Cork Ireland

• Dennis Guilfoyle, PhD, Senior Director,Microbiology and Analytical RegulatoryCompliance, Johnson & Johnson

• Patricia Hughes, PhD, Team Leader,Biotech Manufacturing, CDER, FDA

• David Hussong, PhD, SeniorConsultant, Microbiology andRegulatory, ValSource and Chair, USP Microbiology Expert Committee

• Michael Kurilla, MD, PhD, Director,Office of BioDefense Research AffairNIAID, NIH

• Anil Sawant, PhD, Vice President,Enterprise Regulatory Compliance,Johnson & Johnson

• CAPT Sharon Thoma, PharmD, National Expert, PharmaceuticalInspections, ORA, FDA

Take advantage of the many opportunities to network, interact, share and learn from the experts through Q&As, interactive sessions, poster presentations, vendor exhibits and educational workshops.

Learn more and register at pda.org/microbiology2015.

2015 Theme: Promoting Excellence: Past Lessons, Present Solutions and Future Visions

Register by September 8, 2015

and save up to $200!

3-4 November 2015 Austria Center ViennaVienna | Austria

The Universe of Pre-filled Syringes& Injection Devices

The Parenteral Drug Association presents:

2015 PDA Europe

Make sure to be part of the World‘s largest event on this subject. Register now and save!

2 November | Pre-Conference Workshops 5-6 November | Education Program3-4 November | Conference, Exhibition europe.pda.org/UPS2015

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EUROPE

CMC/REVIEW

IMP Public Consultations

The EU Commission has published four new public consultations on investigational medicinal products (IMPs) covering both GMPs and GCPs for human medicinal products: ● the “commission delegated act on principles and guidelines on good manu-facturing practices for investigational medicinal products for human use and inspection procedures” seeks stakeholder feedback on eight questions and includes a new requirement for regulatory inspections of IMP manufacturers located in third countries to document that the GMPs are equivalent to those in the EU ● the “detailed commission guidelines on good manufacturing practices for investigational medicinal products” complement and expand on the delegated act ● the “commission implementing act on principles and guidelines on good manufacturing practice for medicinal products for human use” seeks input from stake-holders on implementation, and ● the “detailed arrangement for clinical trials inspection procedures including the qualifications and training requirements for inspectors,” which seeks input on the topic described in the title. The consultation period ends on November 24.

EMA Revised Guidelines for Fast-Track Approval

The European Medicines Agency (EMA) announced the release of revised draft guidelines on accelerated assessments and con-ditional marketing authorizations – processes that are important to its efforts to cut drug approval times. Provided is additional guidance regarding: ● areas that have delayed applications in the past ● how to show that a product meets an unmet medical need ● what data is needed to substantiate a positive benefit-risk balance using limited data, and ● what data companies should include in annual renewal submissions under the conditional authorization pathway. The revised guidelines are open for com-ment until the end of September.

EMA ATMP Recommendations

In late August, EMA posted recommendations on the classification of various types of advanced-therapy medicinal products (ATMPs) as a somatic cell therapy, tissue-engineered treatment, or a gene therapy, which includes a rationale for the recommen-dation. In addition, the agency clarified that in vitro-derived platelets fall outside of the scope of the ATMP classifications because they lack a nucleus, and as such are not considered cells.

EMA Electronic Applications

Beginning on July 1, centralized marketing applications for human and veterinary medicines filed with the European Medicines Agency (EMA) are required to be submitted electronically using the agency’s new electronic Application Forms (eAFs). Accord-ing to the EMA press release, the forms “reflect and capture the same content as the previous paper-based versions, but offer a more structured application process for users. Their use is expected to reduce the administrative burden for both the regulatory authorities and pharmaceutical companies.” Beginning in January, eAFs will be mandatory for all marketing applications, in-cluding those using decentralized and mutual recognition procedures, and for national submissions.

EU/Swiss Regulator Confidentiality Agreement

The European Medicines Agency (EMA) and the European Commission’s Directorate General for Health and Food Safety (DG SANTE) have agreed with the Swiss Agency for Therapeutic Products (Swissmedic) and the Swiss Federal Department of Home Affairs (FDHA) to share non-public information on the safety, quality and efficacy of medicines already authorized or under re-view in both Switzerland and in the European Union (EU) in order to enhance public health protection. The agreement is valid for five years.

http://ec.europa.eu/health/human-use/clinical-trials/developments/index_en.htm




http://ec.europa.eu/health/human-use/quality/developements/index_en.htm

http://ec.europa.eu/health/human-use/quality/developements/index_en.htm



http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2015/07/news_detail_002381.jsp&mid=WC0b01ac058004d5c1

http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2015/07/WC500190554.pdf



http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000301.jsp&mid=WC0b01ac05800862c0

http://esubmission.ema.europa.eu/eaf/index.html


https://www.swissmedic.ch/ueber/01398/01401/01936/02070/index.html?lang=de&download=NHzLpZeg7t,lnp6I0NTU042l2Z6ln1acy4Zn4Z2qZpnO2Yuq2Z6gpJCDd3x9f2ym162epYbg2c_JjKbNoKSn6A--


JULY/AUGUST 2015 �� ......... ....


PhEur Monograph on Biological Indicators

In late July, the European Pharmacopeia (PhEur) has made available for comment a revised draft monograph on “biological indicators in the preparation of sterile products,” which replaces a draft published in 2011 that received extensive comments. Changes from the 2011 draft include: ● clarification that the monograph does not apply for biological indicators used to validate the sterility of pipework and other non-terminal units ● a description of a four acceptable indicators along with their quality and user requirements ● removal of the requirement to use biological indicators for ionizing radiation sterilization, and ● a list of characteristics of the lipopolysaccharide preparation acceptable for use as indicators for depyrogenation processes. Comments are due by September 30.

PhEur Clarification on Elemental Impurities

In early August, the European Pharmacopeia (PhEur) provided clarification on its requirements for heavy metals testing for prod-ucts outside the scope of ICH Q3D, which the pharmacopeia incorporated in April of this year. For products outside the scope of the ICH Q3D guideline such as products for veterinary use, PhEur explains, the absence of elemental impurities tests from an individual monograph on a substance used for their production does not release manufacturers from the need to control the level of such elements in their products, where relevant.

GMP/INSPECTION

FMD Safety Features Draft

In mid-August, the EU Commission released a late-stage draft of the Safety Features Delegated Act, which details expectations for product authenticity and anti-counterfeiting features on drug products sold in the EU, as part of its implementation of the Falsified Medicines Directive (FMD). Also released was a draft of an annex detailing what products will be impacted. Once the documents are published in the official journal of the EU, the three-year clock for coming into compliance begins. The date of formal publication has not been announced. The key features – for example, regarding unique identifiers, tamper evidence, verification at the point-of-dispensing, and a Europe-wide system with full interoperability across central and national systems – have not changed since the 2011 draft (see IPQ “Monthly Update” May 2011, pp. 27-35). However, some clarification hasbeen provided – for example, regarding who would set up and assume responsibility for the repositories and the upload of the serialized pack data. While earlier versions assigned that responsibility to “manufacturers,” this version clarifies that the responsible party is the marketing authorization holder.

EU Parallel Distribution Database

In mid-July, the European Medicines Agency (EMA) announced the availability of a public register of parallel distribution no-tices, which aims to provide more transparent access to information on centrally-authorized medicines put on the market by means of parallel trade in the European Union (EU). The register enables EU regulators, parallel distributors, the pharmaceutical industry, patients, and healthcare professionals to identify and have details on all centrally-authorized medicines that are con-sidered compliant with the requirements for parallel distribution. The register currently holds over 15,000 notices and will be updated monthly.

Brazil and Israel Added to EU API Approval List

The European Commission (EC) announced that Brazil and Israel have been added to its list of countries that may export active pharmaceutical ingredients (APIs) into the EU without an accompanying certificate of GMP compliance. Brazil and Israel join Australia, Japan, Switzerland, and the U.S. on the list of countries whose GMP compliance systems have been deemed equivalent to that of the EU member states and do not require certificates of GMP compliance to accompany individual batches of API.

http://pharmeuropa.edqm.eu/TextsForComment/

https://www.edqm.eu/medias/fichiers/ph_eur_policy_on_elemental_impurities_clarification_for_products_outside_the_scope_of_the_ich_q3d_gu.pdf

https://www.edqm.eu/medias/fichiers/elemental_impurities.pdf

http://www.ipqpubs.com/wp-content/uploads/2015/09/FMD-DA_August_2015.pdf

http://www.ipqpubs.com/wp-content/uploads/2015/09/FMD-annex_August_2015.pdf

http://www.ipqpubs.com/issues/ipq-monthly-update-may-2011/


https://fmapps.emea.europa.eu/paradist/index.php

http://ec.europa.eu/health/files/eudralex/vol-1/dec_2015_1057/dec_2015_1057_en.pdf




Tissue Establishment Inspection in Europe

The EU Commission has released an “Operational Manual for Competent Authorities” addressing the inspection of tissue and cell procurement facilities. It covers: ● inspection, accreditation, designation, authorization or licensing of tissue establishments (TEs) ● inspection and authorization of the conditions for tissue and cell procurement ● inspection and authorization of prepara-tion processes for tissues and cells ● inspection and authorization of importing tissue establishments (ITEs), and ● inspection of third country suppliers (3CS) and export activities. The manual, it notes, “is intended to support member states that are establish-ing such regulatory systems for the first time. It should also promote standardization of regulatory systems that are already well established in the European Union.” It further states that the manual was established for information purposes only, and is not legally binding.

EU GMP and GDP Non-Compliance Findings

In July, EU inspectors cited pharma companies in India, China, and France, for non-compliance with EU GMPs, as reported in the Eudra GMDP database. The following are the companies and the primary deficiencies reported:

● Parabolic Drugs (APIs), in Haryana, India, cited for “critical and major deviations” involving adequate storage and controlof documents and samples and material, falsification of documents and data, and integrity and security of data in the QC laboratory.● Wuxi Jida Pharmaceuticals (sterile APIs), in Jiangsu Province, Jiangsu City, China, cited for major deficiencies involvingsterility assurance and a risk of contamination of the product, “inconsistent and conflicting answers on the same topic from both personnel and management,” and company management non-compliance with gowning procedures during the inspec-tion tour. ● Jinan Jinda Pharmaceutical Chemistry Co. (APIs), in Zhangqiu, China, cited for a “critical deficiency” regarding an “unof-ficial and non-controlled storage area containing mainly raw materials and finished products which had been made inacces-sible to inspectors as the door had been removed and replaced with a panel fixed with screws to the wall, which during the inspection the company was requested to remove.” Also cited were “major” deficiencies related to training, cleaning valida-tion, breaches of data integrity in the context of HPLC analysis, microbiological laboratory, and qualification of the contract manufacturer of a key intermediate.● Txcell (cell and tissue therapies), in Besancon, France, cited for aseptic practices, open deviations regarding molds discov-ered during environmental monitoring (EM), and EM alert limits for clean rooms.

In addition, also in July, Czech health authorities issued a GDP non-compliance statement against a D-Pharm, a distributor in the Czech Republic, stating only that the firm “does not comply with the Good Distribution Practice requirements referred to in Article 84 of Directive 2001/83/EC.”

MHRA Data Integrity Blog

The U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA) has established a blog on the topic of data integrity. In the blog, MHRA Expert GMP Inspector David Churchward discusses the importance of data integrity and the common mis-conception that data integrity issues generally indicate that fraud is taking place. He notes that “in the collective experience of my colleagues and me, the majority of issues relate to bad practice, poor organizational behavior, and weak systems, which create opportunities for data to be manipulated. However there is a way for companies to navigate the troubled waters of data integrity deficiencies by taking some basic behavioral, procedural and technical steps to significantly improve their systems.” Churchward proceeds to discuss the importance of company culture, establishing data criticality, inherent integrity risk, and data lifecycles. He also points to MHRA’s data integrity guidance published earlier in 2015.

MHRA License Suspensions

MHRA has suspended licenses for about 700 non-critical generic drugs for which authorization was based on clinical studies con-ducted at GVK Biosciences’ site in Hyderabad, India. Licenses for those that are deemed critical to continuity of supply in the EU have not been suspended. The action was supported by the European Commission based on findings from a 2014 French medi-cines agency (ANSM) inspection of the facility that “cast doubt on the way clinical trials were performed at the site and therefore the reliability of bioequivalency data used to support the granting of a medicine’s license.” However, MHRA noted, “there is no evidence that these medicines are unsafe and people should continue to take them.” In response to the license suspensions, the Indian government has delayed free trade agreement talks scheduled with the EU, the Economic Times of India reported.

http://ec.europa.eu/health/blood_tissues_organs/docs/manual_11_en.pdf

http://eudragmdp.ema.europa.eu/inspections/gmpc/searchGMPNonCompliance.do

http://eudragmdp.ema.europa.eu/inspections/view/gdp/viewGDPCertificate.xhtml

https://mhrainspectorate.blog.gov.uk/2015/06/25/good-manufacturing-practice-gmp-data-integrity-a-new-look-at-an-old-topic-part-1/

https://www.gov.uk/government/publications/good-manufacturing-practice-data-integrity-definitions

https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/451289/Critical_and_non_critical_suspended_products.pdf

http://ec.europa.eu/transparency/regdoc/rep/3/2015/EN/3-2015-5100-EN-F1-1.PDF

https://www.gov.uk/government/news/gvk-biosciences-mhra-responds-to-european-medicines-agencys-recommendation-to-suspend-medicines

http://articles.economictimes.indiatimes.com/2015-08-07/news/65317777_1_indian-pharmaceutical-alliance-ipa-generic-medicines

Strategic compliance and riSk management

PAREXEL® ConsuLting:

© 2014 PAREXEL International Corporation. All rights reserved.

Regulatory bodies around the world are getting more aggressive in their enforcement, with biopharmaceutical and medical device companies giving careful consideration to both proactive and reactive strategies and implementation. In addition to over 50 full-time experts, representing one of the industry’s most distinguished practices, PAREXEL offers a strong bench of highly qualified independent consultants, allowing us to deliver the level of service you need, cost effectively.

Please reach out to us at [email protected] if you would like further information about our portfolio of services or the mix of expertise we offer.

3138 N. 10th Street, Suite 500, Arlington, VA 22201 • Phone: 571-814-3449 E-mail: [email protected]

Are YOU ready? Completion of risk assessment of all excipients used in European drugs due by March 2016! Attend the Risk Assessment-

Linked Workshops November 10-12, 2015 in Arlington, VA

The European Union has issued a Falsified Medicines Directive, "Guideline of 19 March 2015 on the formalized risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use." The global impact to both excipient makers and users is profound.

By March 21, 2016 pharmaceutical manufacturers supplying to Europe must perform a risk assessment of each of their excipient suppliers to determine the GMP expectations. The "data/evidence to support the gap analysis should be obtained through audit or from information received from the excipient manufacturer."

The Risk Assessment Workshop will give you the tools to perform the gap analysis based on site audit or review of the supplier Excipient Information Package so you CAN be ready.

REGISTER (for all 3 days or the session that’s best for you) 3 Workshops on Risk Assessment Nov.10-12, 2015 Arlington, VA Risk Assessment and Quality Risk Management are new components of Excipient Quality Systems. This workshop series is an excellent, hands on opportunity to become more familiar with risk assessment, validation, and significant change evaluation as they relate to excipient quality.

Fees Who Should Attend Register for all 3 days or the session that best suits your learning needs. Discounted registration fees for more than one workshop.

IPEC-Americas Members: 1 day - $700 2 days - $1190 3 days - $1680

Non Members: 1 day - $950 2 days - $1615 3 days - $2280

Click here for more information: http://ipecamericas.org/content/risk-assessment-significant-change-validation

Everyone involved in excipient manufacture, quality assurance and related functions as well as the use or distribution of excipients.

Day 1 Quality Risk Management and Risk Assessment – An overview

Day 2 Qualification/Validation-Using Risk Assessment for Re-validation

Day 3 Significant Change – Using Risk Assessment to Evaluate Changes in Process and Elsewere


https://www.ipec-events.com/index.asp?Id=37

http://ipecamericas.org/content/risk-assessment-significant-change-validation

http://ipecamericas.org/content/risk-assessment-significant-change-validation

Jerry

Rectangle


JULY/AUGUST 2015 �1 ......... ....


INTERNATIONAL

CMC/REVIEW

ICH M7 Addendum

ICH has issued an addendum to its M7 guidance on “assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk” that includes examples of calculations for acceptable intake (AI) and permitted daily exposure (PDE) for 15 compounds commonly used in pharmaceutical manufacturing. The calculations are accompanied by the rationale used to derive them. Also included is an extensive list of publications covering tox studies of each compound. The examples should help firms in implementation of the M7 guideline, which have proven challenging to the industry (see IPQ “Monthly Update October 2014, pp. 32-38). The M7 addendum was published in early July as a Step 2 document and is out for comment until January 31, 2016.

Nano-Crystal Medicines

The National Institute of Pharmaceutical Education and Research (NIPER) of India has created and licensed technologies for producing nano crystal-based medicines, In-Pharma Technologist reports. Involved are the use of nano-based crystals directly as a solid powder using a novel spray-drying system that generates solid particles dispersed in excipients. The technology, NIPER says, is especially applicable to producing forms of insoluble orally-administered drugs that can be more readily absorbed in the human body.

TGA Adopts EU Guidelines

TGA announced that it has completed a process begun in 2011 (see IPQ October 22, 2011) of adopting a number of EU and ICH guidelines. Among these are ten guidelines that include ICH Q9 and Q10, in addition to other quality, stability, active substance, and clinical and non-clinical guidelines. All became effective at the end of May.

CFDA Drug Approval Process

China will begin major reforms to its drug review and approval process, according to a mid-August announcement from Chi-na’s State Council. Included in the reforms are: ● the launch of a pilot program reflecting the European marketing authorization holder (“MAH”) model for drugs ● allowing synchronous in-country clinical trials for new drugs that have not yet been marketed overseas, and ● adopting qualified clinical data obtained directly from multicenter clinical trials.

Audits of Application Data in CFDA Submissions

CFDA is requiring firms that have submitted drug applications to self-audit the clinical trial portions of the application to ensure that there are no data integrity issues, South China Morning Post reports. CFDA has experienced issues with drugs on the market in China being reported as ineffective, and has targeted the integrity of clinical trial data as a possible contributing factor. Firms will have until August 25 to submit the self-audit reports and allow the application approval process to continue, or will have to withdraw the applications by that date. CFDA said that 1,622 applications would be subject to self-inspection – 171 imported drugs, 948 new domestic drugs and 503 drugs which already had national specifications.

Shanghai Drug Evaluation Center

In an effort to speed new drug approvals in China and to keep and attract drug and device companies, China’s FDA (CFDA) is setting up a regional center for drug evaluation in Shanghai, CCTV reports. In May, CFDA increased the fees to register medi-cines and devices as part of its efforts to fund faster approvals. CFDA is also encouraging pharmaceutical companies to set up their research centers in Shanghai. A timeframe for opening the center was not released.

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_Addendum_Step_2.pdf



http://www.in-pharmatechnologist.com/Processing/NIPER-says-API-nano-crystal-formulation-tech-will-cut-drug-costs/?utm_source=newsletter_weekly&utm_medium=email&utm_campaign=From%2028-Aug-2015%20to%2004-Sep-2015&c=EDte3655CZL1R70ahfrxJqhdpL2Fx%2Bvz&p2=

http://www.ipqpubs.com/cmc-standards/australia%E2%80%99s-tga-proposes-adoption-of-several-euich-guidelines/

http://www.tga.gov.au/consultation/consultations-adoption-european-union-guidelines-australia-outcome-previous-consultation

http://english.gov.cn/statecouncil/

http://english.gov.cn/statecouncil/

http://www.scmp.com/news/china/policies-politics/article/1843559/china-scrutinise-clinical-drug-trial-claims

http://english.cntv.cn/2015/07/14/VIDE1436823600884592.shtml




GMP/INSPECTION

PIC/S Annex 15 Revision

PIC/S has announced that it has adopted, by procedure, the EU Annex 15 revision (see IPQ “Monthly Update” Jan,/Feb. 2013, pp. 24-30). Annex 15 describes the principles of qualification and validation which are applicable to the facilities, equipment, utilities and processes used for the manufacture of medicinal products from a GMP vantage point, and may also be used as supplemen-tary optional guidance for active substances. The annex was approved by the EU in March and will go into effect on October 1.

WHO Biologic Product Guide Revision

The World Health Organization (WHO) has produced a draft revision of its GMPs for biological products based on input from a group of national regulatory authorities, national control laboratories, manufacturers, and academia researchers that was con-vened in July. The guideline applies to the commercial manufacture, control and testing of biological products from starting materials and preparations, including seed lots, cell banks and intermediates, through to the finished products. Manufacturing procedures within the scope of these guidelines include: ● growth of strains of microorganisms and eukaryotic cells ● extraction of substances from biological tissues, including human, animal and plant tissues and fungi ● recombinant DNA (rDNA) tech-niques ● hybridoma techniques, and ● propagation of microorganisms in embryos or animals. The draft is out for comment until September 14, 2015.

ASTM Continuous Processing Guide

ASTM has made available a guide on the application of continuous processing in the pharmaceutical industry. It explains that although some continuous processing is used in the pharmaceutical industry, generally in individual unit operations, such op-erations “do not deliver the potential benefits of an integrated continuous manufacturing operation.” The guide introduces key concepts and principles to assist in the appropriate selection, development and operation of continuous processing technologies for the manufacture of pharmaceutical products, with particular consideration to the development and application of the “ap-propriate scientific understanding and engineering principles that differentiate continuous manufacture from traditional batch manufacturing.” Included is an appendix that compares the characteristics of continuous and discrete or batch processes.

TGA GMP Application Clearance Process

TGA announced at the end of July that it has made improvements in its GMP application clearance process, particularly regard-ing applications from manufacturers located in countries that have mutual recognition agreements (MRAs) with Australia. It notes that in mid-July 2015, 90% of application clearances were approved in 19 weeks, compared to 24 weeks one month earlier.

Bar Coding in India

In July, the Indian government began requiring bar codes on individual packages of drugs shipped out of the country in an effort to shore up the reputation of its pharmaceutical industry, the Economic Times reports. Bar-coding of mono cartons, which hold primary packs of drugs, will enable them to be traced back to the source, the ministry of commerce said in an order. Drug makers will also have to maintain evidence in a central portal, maintained by the Indian government. The health ministry is considering a similar move for drugs sold within the country. “The measure is in line with highest global standards. Barcoding on the mono carton is a step further to trace the origin of a particular drug. This will help build clean reputation of Indian pharma in the inter-national market,” a government official told the Economic Times.

India Sampling of Imported APIs and Ingredients

India’s Central Drugs Standard Control Organization (CDSCO) has completed its sampling of domestic drug manufacturers (see IPQ August 15, 2014) and is turning its attention to ingredients entering the country. PharmaBiz reports that CDSCO and the National Institute of Biologicals (NIB) are working together on the program. The first major step was the reallocation of CDSCO assistant drugs controllers from the regulator’s head office to its operations at 12 ports where the sampling will take place.

http://www.tga.gov.au/gmp-clearance-application-process-improvements

http://ec.europa.eu/health/files/eudralex/vol-4/2015-10_annex15.pdf

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

http://www.who.int/biologicals/BS2253_GMP_For_Biologicals_clean.pdf

http://www.astm.org/Standards/E2968.htm

http://articles.economictimes.indiatimes.com/2015-04-13/news/61103112_1_mono-indian-pharma-alliance-fake-drugs

http://www.ipqpubs.com/gmp-policy/india-to-launch-nationwide-study-on-substandard-drugs/

http://www.pharmabiz.com/NewsDetails.aspx?aid=89322&sid=1

http://www.cdsco.nic.in/writereaddata/relieving ADC(1).pdf


JULY/AUGUST 2015 �� ......... ....


CFDA Surprise Inspections

On September 1, China will begin regular surprise inspections on pharmaceutical and medical device firms, according to China Food and Drug Administration (CFDA) as reported to Xinhua News. Surprise checks will be launched when authorities are contacted by whistle-blowers from the public or CFDA becomes suspicious of a firm. CFDA also stated that anyone found de-liberately leaking confidential information on inspections or informers will be subject to discipline, and that those involved with suspected criminal acts will also be transferred to judicial departments.

www.usp.org

2nd Synthetic Therapeutic Peptides Workshop – Regulations, Standards and QualityNovember 2, 2015 - November 3, 2015

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

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

Upcoming Workshops:

http://www.usp.org/meetings-courses/workshops/2nd-synthetic-therapeutic-peptides-workshop-regulations-standards-and-quality

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

http://www.usp.org

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

2015 Theme: Focusing on Today’s Challenges to Deliver Tomorrow’s Vaccines

The 2015 PDA/FDA Vaccines Conference will showcase innovative manufacturing approaches and how they are being applied using an exciting new format that will give attendees a truly global perspective on the evolution of the vaccine industry. Co-sponsored by the U.S. FDA, this unique conference will simulcast six presentations between two locations, the U.S. and Europe. Experts will address global technical and regulatory challenges and how to effectively deliver new vaccines to the global patient population. There will be interactive Q&A allowing participants in both locations to ask their most pressing questions.

Hear from regulatory and industry experts about the latest "hot topics" in vaccinology, including:

• The Future of Vaccines and the Impact, Rino Rappuoli, PhD, Global Head, Vaccines Research, Novartis Vaccines

• Development of Vaccines from a Government Perspective, Kathryn Zoon, PhD, Director, Intramural Research, NIAID, NIH

• Ebola Vaccinations – Where Are We Now, Cliff Lane, MD, Deputy Director, Clinical Research and Special Projects, NIAID, NIH

• Clinical Trials and IRBs in Developing Countries, Penny Heaton, Director, Vaccine Development, Global Health Program, Bill and Melinda Gates Foundation

• And many more!

Be part of the global solution — prepare for emerging trends in vaccine development and manufacturing. Learn more and register at pda.org/vaccines2015

Are you looking for an individualized learning experience? PDA Education brings you the 2015 Vaccines Course Series on December 3-4 at the Bethesda North Marriott Hotel and Conference Center.

Choose from the following offerings:

Current Challenges in Vaccines (Dec. 3)Learn the complexities and unique challenges of the vaccine field and gain a basis for assessing and proposing resolutions to manufacturing and quality issues. Case studies will underline topics of particular interest to the field today.

Modern Manufacturing and Trend Monitoring Techniques for Vaccines (Dec. 4) Obtain an overall understanding of effective methods for vaccine manufacturing processes and how to maximize controls to meet and exceed current international regulatory expectations.

For more information and to register for the 2015 Vaccines Course Series, visit pda.org/vaccinescourses

PDA Europe will host the 2015 Europe Vaccines Conference

concurrently, December 1-2 in Berlin, Germany, which will take an in-depth look

at other emerging topics in vaccines.




FDA Drug GMP Warning Letters and Recalls Posted in July/August

Warning Letters

Company Name Location Letter Date

Product Type

Areas Cited

International

Mahendra Chemicals

India 7/13/2015 API ● data integrity ● raw data destruction ● training ●computer controls

Spira Labs India 7/23/2015 Contract testing lab

● test method validation ● following SOPs ● OOSinvestigations

NOTE: The two drug GMP warning letters posted by FDA in July were both to firms in India. The letter to API manufacturer Ma-hendra Chemicals cited data integrity concerns involving the use of uncontrolled loose paper to capture critical manufacturing data that were destroyed after transcription into the batch production records and copies of raw lab instrument data in a recycle bin. Also of concern was a lack of training of operations personnel. A central concern in the letter to contract testing lab Spira was method validation, including ten methods identified in a 2011 inspection as not validated that remain unvalidated. The let-ter also maintains that the firm’s SOPs “do not adequately address the need to investigate anomalies, unexpected events, or out-of-trend results.”Mylan India 8/6/2015 Sterile

injectables● aseptic process validation ● sterilization validation● gowning ● environmental monitoring ● personnelmonitoring ● media fills ● smoke studies ● sampling plans ● pressure differentials ● failure investigations ● computer controls ● complaint investigations

NOTE: The 14-page warning letter to Mylan covers three sites in India, including two purchased from Agila Specialties in De-cember 2013, and cites inspections from August and September 2014 (at the two former Agila Sites) and February 2015 (at the Mylan site). The central concerns at all three plants involve practices, procedures, and behaviors that call into question the sterility of the products being produced, including: ● the quality of gloves used in sterile areas that investigators said often had holes in them ● a lack of smoke studies ● hundreds of out-of-action-level (OAL) microbial testing results, and ● a lack of inves-tigations of customer complaints of tainted products to find and fix the associated problems. In the letter, the agency states that “these items found at three different sites…raise questions about the ability of your current corporate quality system to achieve overall compliance with CGMP. Furthermore, several violations are recurrent and long-standing. Although we acknowledge that the Agila facilities were acquired by Mylan recently, you were on notice of the violations in Warning Letter 320-13-26, dated September 9, 2013. Even without this Warning Letter, your corporate quality system should have detected and corrected the forgoing violations without FDA intervention.”

The following are the drug GMP warning letters posted by FDA during July/August, 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.

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm455345.htm



CMC Strategy Forum Europe 20169-11 May 2016, Marriott Rive Gauche Hotel, Paris, France

CMC Strategy Forum: Drug Product Validation and ComparabilityJuly 18-19, 2016, Gaithersburg Marriott Hotel, Gaithersburg, MD

Bioassays 2016: Scientific Approaches and Regulatory StrategiesApril 4–5, 2016, DoubleTree by Hilton Hotel Washington DC Silver Spring, Silver Spring, MDABSTRACT SUBMISSION DEADLINE: March 15, 2016 poster presentation

CMC Strategy Forum Japan 2015 9-10 November 2015, Tokyo Marriott Hotel, Tokyo, Japan

WCBP 2016: 20th Symposium on the Interface of Regulatory and Analytical Sciences for Biotechnology Health ProductsJanuary 26-28, 2016, The Mayflower Hotel, Washington, DCABSTRACT SUBMISSION DEADLINE: November 18, 2015 poster presentation

Analytical Technologies Europe: Symposium on the Practical Applications including CE, LC and MS in the Biopharmaceutical Industry15-18 March 2016, Imperial Riding School Renaissance Hotel, Vienna, AustriaABSTRACT SUBMISSION DEADLINE: 18 December 2015 oral presentation

12 February 2016 poster presentation

5th International Symposium on Higher Order Structure of Protein TherapeuticsApril 11-13, 2016, Renaissance Long Beach Hotel, Long Beach, CA ABSTRACT SUBMISSION DEADLINE: January 15, 2016 oral presentation

March 11, 2016 poster presentation

CMC Strategy Forum: Parallel ForumsChange Happens: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management -and- Cell Line Selection and Control of Product Consistency during Cell Cultivation - Myths, Risks and Best PracticesJanuary 25, 2016, The Mayflower Hotel, Washington DC

CALENDAR OF EVENTSFor all program updates, on-line registration, abstract submission, information on exhibiting and/or sponsoring, please visit the CASSS Web site at www.casss.org.

SEPTEMBER 2015 – JULY 2016

SCANto view all updates at casss.org

12th Symposium on the Practical Applications of Mass Spectrometry in the Biotechnology IndustrySeptember 22-25, 2015, New York Marriott at the Brooklyn Bridge, Brooklyn, NYABSTRACT SUBMISSION DEADLINE: August 21, 2015 poster presentation

CE in the Biotechnology & Pharmaceutical Industries: 17th Symposium on the Practical Applications for the Analysis of Proteins, Nucleotides and Small MoleculesSeptember 20-24, 2015, New York Marriott at the Brooklyn Bridge, Brooklyn, NYABSTRACT SUBMISSION DEADLINE: August 21, 2015 poster presentation


JULY/AUGUST 2015 �� ......... ....


Recalls in July/August

JulyProduct Recaller # of

LotsClass Reason

Compliance with NDA/Monograph RequirementsSlim-K caps Bethel

Nutritional Consulting

One I Marketed Without An Approved NDA/ANDA: Product was found to contain sibutramine, desmethylsibutramine and phenolphtha-lein based on FDA sampling and analysis.

Contamination / Lack of Sterility AssuranceVarious com-pounded IV sol.

Lincare Numer-ous

II Lack of Assurance of Sterility.

Sodium chloride inj.

Hospira 2 II Lack of assurance of sterility: Potential channel leaks near the threaded vial port.

DissolutionCapecitabine tabs

Mylan One II Failed Dissolution Specifications: low out-of-specification (OOS) results for dissolution were obtained at the nine-month stability point.

Disulfiram tabs Qualitest 3 III Failed Dissolution Specifications: During routine stability testing at the 12 month time point, one product lot was found to be out of specification for dissolution.

Zolpidem tabs Purdue Pharma

One III Failed Dissolution Specifications

GMP / GDPVarious caps and tabs

Wockhardt >100 II CGMP Deviations: Firm did not adequately investigate customer complaints.

Carb-O-Philic �0 Cream

Geritrex 3 III CGMP Deviation: Poor container closure of the bulk storage container.

ImpurityRifampin inj. Fresenius Kabi 2 II Failed impurities/degradation specifications; two lots are out-of-

specification for impurities and color.Nitroglycerin transdermal system

Kremers Urban Pharma

2 II Failed Impurities/degradation specifications: failed specification for unknown impurity at the 24 month stability testing.

Labeling / PackagingLevonorgestrel/ethinyl estradiol tabs

Actavis 26 III Labeling: Incorrect or Missing Package Insert; Product is being recalled because the birth control packs were distributed with out-dated package inserts.

Desmopressin tabs

American Home Packag-ing

One III Tablets/Capsules Imprinted with Wrong ID: Some tablets incor-rectly imprinted with an X on one side.

The following is a listing of the drug product recalls included in FDA’s weekly “Enforcement Reports” issued during July/August. Included are the generic names of the products, the dosage form, the manu-facturer, 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.accessdata.fda.gov/scripts/enforcement/enforce_rpt-Product-Tabs.cfm?action=select&recall_number=D-1207-2015&w=07152015&lang=eng




http://www.accessdata.fda.gov/scripts/enforcement/enforce_rpt-Product-Tabs.cfm?action=select&recall_number=D1151-2015&w=07082015&lang=eng


http://www.ipqpubs.com/wp-content/uploads/2015/09/Wockhardt-July-2015-recalls.pdf









Particulate

Various LVP products

Baxter 15 I Presence of Particulate Matter: Products recalled due to pres-ence of particulate matter (metal).

Fluorouracil inj. Teva 8 I Presence of Particulate Matter: Black particulate matter was identified as aggregate of silicone rubber pieces from a filler diaphragm and fluorouracil crystals.

Bupivacaine inj. Hospira One I Presence of Particulate Matter: Presence of free-floating and embedded iron oxide particles.

Potency / Content Uniformity

Oxycodone tabs Harvard Drug Group

2 II Superpotent Drug: Confirmed customer complaint of a single unit dose blister cavity containing 2 oxycodone HCl 5 mg tab-lets.

Losartan tabs Apotex 4 II Failed Content Uniformity Specifications: The product may not meet the limit for blend uniformity specification.

Enalapril/ hydro-chlorothiazide tabs

Apotex One II Failed Content Uniformity Specifications: The product may not meet the limit for blend uniformity specification.

Analgesic cream BioComp Pharma

One III Subpotent Drug: menthol and methyl salicylate below specifica-tion.

Cortisol caps Abrams Royal Pharmacy

One III Failed Content Uniformity Specifications: Failed Uniformity of Dosage Units specifications.

Analgesic gel Indiana Bo-tanic Gardens

One III Superpotent Drug: Product may not be uniformly blended result-ing in non-uniform distribution of the active ingredient menthol.

Other Spec NonconformanceKetorolac tro-methamine inj.

Hospira 63 II Crystallization; identified as calcium salt of Ketorolac.

Naltrexone and bupropion ER tabs

Takeda One II Failed Tablet/Capsule Specifications: Potential tablet defect of broken tablets and/or equatorial splitting of the bilayer tablets into the two drug components.

Magnesium sul-fate inj.

Hospira One III Failed pH Specifications: 12 month stability testing.

Dry barium sul-fate for susp.

Bracco Diag-nostics

2 III Failed stability specifications: This recall has been initiated due to out of specification results for viscosity.

Hydroxyzine tabs

Qualitest 8 III Failed Tablet/Capsule Specifications; The identification codes on some tablets may be unreadable.















Protecting Patients WorldwideProtecting Patients WorldwideProtecting Patients WorldwideProtecting Patients WorldwideProtecting Patients Worldwide®®

+1 (202) 230-5608 • [email protected] • www.rx-360.org+1 (202) 230-5608 • [email protected] • www.rx-360.org+1 (202) 230-5608 • [email protected] • www.rx-360.org+1 (202) 230-5608 • [email protected] • www.rx-360.org+1 (202) 230-5608 • [email protected] • www.rx-360.org+1 (202) 230-5608 • [email protected] • www.rx-360.org+1 (202) 230-5608 • [email protected] • www.rx-360.org

We the undersigned members of Rx-360 fully support the mission of Rx-360 which is to:

PROTECT PATIENT SAFETY BY SHARING INFORMATION AND

DEVELOPING PROCESSES RELATED TO THE INTEGRITY OF THE

HEALTHCARE SUPPLY CHAIN AND THE QUALITY OF MATERIALS WITHIN THE SUPPLY CHAIN.

ABBVIE • AMGEN • AMPAC FINE CHEMICALS • ASH STEVENS • ASTRAZENECA • AURISCO PHARMACEUTICAL CO. LTD. • AVANTOR • BASF • BAXTER • BAYER • BEND RESEARCH • BIOGEN IDEC • BO

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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




JULY/AUGUST 2015 �� ......... ....


August

Product Recaller # of Lots

Class Reason

Compliance with NDA/Monograph RequirementsJoint formula caps

GC Natural Nutrition

All I Marketed Without An Approved NDA/ANDA: Product was found to contain undeclared diclofenac, a prescription non-steroidal anti-inflammatory drug, and chlorpheniramine, an over-the-counter antihistimine, making this an unapproved drug.

Contamination / Lack of Sterility Assurance

Various com-pounded IV sols.

The Apoth-ecary Shoppe

46 II Lack of Assurance of Sterility: Due to lack of documentation of proper environmental monitoring during the time in which the medication was produced.

Bromfenac oph-thalmic sol.

Bausch & Lomb

One II Lack of Assurance of Sterility: Failed preservative effectiveness testing.

DissolutionMoexipril tabs UCB One II Failed Dissolution Testing: Failed 24 month dissolution testing.

Nisoldipine ER tabs

Shionogi 2 II Failed Dissolution Specifications.

Rivastigmine tartrate caps.

Dr. Reddy’s One II Failed Dissolution Specifications: Out-of-specification results for dissolution found.

Acetaminophen tabs

GlaxoSmith-Kline

14 III Failed Dissolution Specifications.

Bupropion ER tabs

Sun Pharma 3 III Failed Dissolution Specification: During analysis of the 18 month long term stability testing, it was noticed that the drug release results at the 4 hour time point are not meeting specifications.

GMP/GDPClonidine tabs Mutual Phar-

maceutical18 II cGMP Deviations; Clonidine hydrochloride drug substance used

in the manufacturing of this product, was dispensed in unauthor-ized rooms by the drug substance manufacturer.

Lisinopril tabs Wockhardt 3 II CGMP Deviations: An FDA inspection identified inadequate investigations of past market complaints.

ImpurityDextroamphet-amine/ amphet-amine/dextroam-phetamine tabs

Teva 2 II Failed Impurities/Degradation Specifications: out of specification for unknown impurity.

Labeling / PackagingDesmopressin tabs

Actavis One III Tablets/Capsules Imprinted with Wrong ID: Some tablets incor-rectly imprinted with an X on one side.

Hydralazine inj. Fresenius Kabi One III Incorrect Expiration Date: The “11/06” expiration date printed on the tray (secondary packaging) is incorrect (it should be 11/2016).

Ampicillin caps Qualitest One III Labeling: Incorrect and/or Missing Package Insert: Product is labeled with unapproved labeling.


http://www.ipqpubs.com/wp-content/uploads/2015/09/August-2015-Apothecary-Shoppe-recalls-taken-from-the-FDA-Enforcement-Report.pdf
















Various toothpaste products

Various tooth-paste products

GlaxoSmith-Kline

135 II Presence of Foreign Substance: Fragments of wood found when the product was extruded onto a toothbrush.

Particulate

Methotrexate inj. Mylan 2 I Presence of Particulate Matter: observed during testing of retained samples.

Cytarabine inj. Mylan One I Presence of Particulate Matter: observed during testing of retained samples.

Carboplatin inj. Mylan One I Presence of Particulate Matter: visible foreign particulate matter observed during testing of retention samples.

Gemcitabine inj. Mylan 12 I Presence of Particulate Matter: visible foreign particulate matter observed during testing of retention samples.


Baxter 2 I Presence of Particulate Matter: Customer complaint for an in-sect found free floating inside a single bag for each lot recalled.


Baxter One II Presence of Particulate Matter and Lack of Assurance of Steril-ity: The firm received a complaint for customer of presence of particulate matter, leaky containers, and missing port protectors.

Potency / Content UniformityMometasone ointment

Perrigo 5 III Subpotent drug.

Other Spec NonconformanceIpratropium buterol inhala-tion spray

Boehringer Ingelheim

One II Defective Delivery System: Inhalers do not spray properly, emit-ting either no spray or a short transient spray.

Isotretinoin caps Ranbaxy One II Incorrect/Undeclared Excipients: Product contains undeclared FD&C Yellow No. 5 in the capsule shell.











IPEC-Americas: THE Authority and Resource on Pharmaceutical Excipient Quality and Safety Training

www.ipecamericas.org Fall Webinars are Open for Registration! Registration Fees: $75 IPEC-Americas Members / $150 Non-Members / $50 Govt. Rate Key Topics: After attending this webinar, the participant will be aware of:

• New regulatory implications for Atypical Actives • Appropriate GMPs for manufacture and audit of Atypical Actives • What could happen if regulators apply ICH Q7 API GMPs to manufacture of Atypical Actives • Possible strategies and solutions for ameliorating the above situations

Registration Fees: $75 IPEC-Americas Members / $150 Non-Members / $50 Govt. Rate Awareness Objectives (Key Topics):

• Excipient GDPs – why you should care where your excipients come from • Excipient supplier distinctions – who does what in excipient supply • Utilizing the IPEC GDP Guide for tightening up your ingredient supply chain • EXCiPACT and NSF/IPEC/ANSI-363-2014 Standard - New tools for evaluating and

improving GDPs Registration Fees: $150 IPEC-Americas Members / $300 Non-Members / $100 Govt. Rate Awareness Objectives (Key Topics): At the conclusion of this series, participants should be able to:

• Identify fundamental strategies for preparing eCTD submissions • Explain the technical requirements of eCTD submissions • Demonstrate best practices in the use of MS Word and Adobe Acrobat in preparing content

for eCTD submissions • Determine whether in-house publishing or outsourcing is the solution for submitting a US

eCTD that is compliant with CDER and CBER requirements

Atypical Actives Registration 11AM-1:00PM EDT Oct 14

Good Distribution Practices Registration 11AM-1:00PM EST Nov 11

Filing DMFs in eCTD Format (2 part) Registration 11AM-1:00PM EST Dec 2-3




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