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

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INTERNATIONAL PHARMACEUTICAL QUALITY Inside the Global Regulatory Dialogue

VOL. 4, NO. 6

GMP/INSPECTION

•FDA Data Integrity Concerns Continue in India as Three More Firms Draw GMP Warning Letters..................................2

•FDA Piloting Electronic FARS as Focus Intensifies on Defect Data Mining....................................................................................9

INTERNATIONAL

GMP/INSPECTION

•Burden of Pre-Inspection Submission Requests from Agencies Outside the US and Europe is Growing.............31

•NSF-IPEC GMP Standard Will Provide Risk-Based Approach for Auditing and Certifying Excipient Manufacturers..........................................................................38

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GMP/INSPECTION

•FMD Implementation in Europe Drives Better API Sourcing Knowledge and Interagency Communcations.......................16

•Revision of EU Annex 16 Clarifies QP Responsibilities in the Face of an Increasingly Complex Supply Chain....................22

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FDA Data Integrity Concerns Continue in India as Three More Firms Draw GMP Warning Letters Three warning letters recently issued on findings at facilities in India indicate FDA’s continued focus on data integrity as a central concern of its international inspection program – and in the Indian arena, in particular.

A warning letter sent at the end of May to RPG Life Sciences, headquartered in Mumbai, was followed by letters in July to Germany-based Fresenius Kabi, regarding its facility in Kalyani, and to Wockhardt, regarding its headquarter plant in Aurangabad, that together encompass an array of issues around the integrity of records, procedures and interactions with FDA investigators.

The three warning letters, in turn, follow in the wake of the high-profile revelations from FDA’s investigation of the integrity problems at Ranbaxy plants in India, which resulted in a major consent decree in January 2012 (see IPQ “Monthly Update” February 2012, pp. 23-30) and have continued to garner media attention as more information from a company whistleblower has surfaced. The concerns at Ranbaxy extended into its US marketing applications, with significant consequences on its US product portfolio.

Two other India-based manufacturers, Aurobindo Pharma and Cadila Healthcare, received warning letters in mid-2011 that focused on the integrity of environmental monitoring and microbiology lab data, respectively (see IPQ “Monthly Update” May 2011, pp. 7-9).

The recent warning letters to the three Indian firms are the only ones issued by FDA so far this year that have specifically made reference to “data integrity” as a concern. Data integrity was highlighted by FDA in several other warning letters issued in 2011 and 2012 to companies in China (ibid.), Mexico (see IPQ “Monthly Update” May 2012, pp. 20-25), the United Arab Emirates (UAE) (ibid.), Canada (see IPQ “Monthly Update” January 2012, pp. 28-30) and the US (see IPQ “Monthly Update” April 2013, pp. 16-19 & May 2011, p. 15).

The uptick in the number of data integrity problems that FDA has been finding at manufacturing and testing facilities has prompted the drug compliance office to better define the forms in which the integrity problems can appear and the red flags that will trigger more intensive investigations (see IPQ “Monthly Update” May 2012, pp. 11-15).

If the Data is Troubling, Delete It

FDA’s concern with data integrity at RPG Life Sciences grew out of investigator findings in reviewing the firm’s finished product and API facilities in Ankleshwar and Mumbai, respectively.

During an inspection at Ankleshwar in November 2012, investigators uncovered a pattern at the facility of not: ● identifying, reporting, or investigating out-of-specification

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(OOS) results ● following laboratory control mechanisms and recording and justifying deviations from them ● ensuring that lab records include complete data, and ● exercising appropriate controls over computer systems and access to altering of key records.

FDA cited the firm’s “practice of deleting critical analytical data and backdating records” as “a clear breach in your quality system that raises serious concerns regarding the integrity and reliability of the laboratory data used to release drug products.”

Along with the revision of its password procedure to prevent electronic record manipulation, undertaken by RPG as a corrective action following the inspection, the warning letter calls for the firm to evaluate “the extent and impact of the missing data on the quality of all finished drug products released for distribution.”

A similar pattern of failing to document and investigate OOS results, discarding/deleting raw data, and inadequately controlling computer access was also found at RPG’s API site in Mumbai during a follow-up inspection that ended in February 2013.

Included in the shortfalls found at Mumbai was the lack of investigation of complaints related to foreign particles and impurity overages.

The endemic nature of the existing lab data deletion practices at Mumbai is apparent in FDA’s review of the inspection interactions.

When asked why an OOS residual solvent finding was not reported or investigated but instead deleted from the related electronic records, an analyst “admitted that he also deleted other uninvestigated failing and/or OOS electronic data from the laboratory database in January 2013 prior to our

inspection.” The QC Senior Manager, the letter reports, “also acknowledged this laboratory-wide electronic data deletion practice.”

Further, during the inspection, the analysts at the facility demonstrated to the investigators “that they could delete any electronic analytical data files from the laboratory computers and external backup hard drives.”

RPG affirmed in its response to the Mumbai inspection that it was: ● procuring a centralized server and software that will prevent electronic data deletion ● assigning an individual user ID and password to each analyst, and ● training them not to delete electronic analytical data and to report all lab incidences to managers. The letter states that FDA will be verifying the effectiveness of these steps during the next inspection.

The firm’s practice of discarding OOS lab records, disregarding and deleting OOS data, and selectively reporting only passing results, the warning letter concludes, undermines FDA’s faith in the reliability and integrity of all of the firm’s data, and, together with the other deficiencies found, points to the overall weakness of the firm’s quality system and its corporate management oversight.

The compliance office “strongly” recommended that the RPG management “undertake a comprehensive evaluation” of the global manufacturing operations to ensure compliance with CGMP regulations. The letter also “highly” recommended that the company hire a third party auditor, with experience in detecting data integrity problems, to assist with this evaluation and overall GMP compliance.

“Trial” Sample Testing Flagged

Ten days before beginning its late-January inspection of RPG’s API facility, FDA completed an inspection at Fresenius

FDA’s Data Control Expectations

You are responsible not only for having controls to prevent omissions in data, but also for recording any changes made to existing data, which should include the date of change, identity of the person who made the change, an explanation or reason for the change, and formal documentation as a deviation. Any such changes should also include supervisor evaluation to determine if the change is appropriate, and their concurrence.

QA should also have oversight over your deviations and be fully aware of such events when making their batch dis-position decision. All changes to existing data should be made only when appropriate, and in accordance with an established procedure. It is your responsibility to ensure that data generated during operations is accurate and that the results reported are a true representation of the quality of your APIs.

The following is a description of FDA’s expectations for the control of data and its integrity provided in the warning letter issued in early July to Fresenius Kabi on the shortfalls found at its API facility in West Bengal, India.

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Kabi’s oncology API facility in Kalyani, West Bengal that uncovered a similar range of problems. The findings also undermined FDA’s faith in “the integrity and reliability of the data generated” at the Kalyani plant and, in turn, about the effectiveness of a quality system that did not detect and prevent the problems.

Similarly to FDA’s observations at RPG’s finished product facility in Ankleshwar, the Kalyani facility was found to be designating tests as “trial” runs prior to the official “final” QC analysis and then not retaining, reporting and/or investigating OOS data associated with them. Instead, “only passing results were considered valid, and were used to release batches of APIs intended for US distribution.”

As at RPG, the investigators did not approve of the firm’s electronic data management practices, which “permitted unauthorized changes, as digital computer folders and files could be easily altered or deleted.”

FDA cited the facility’s practice of combining batches that failed impurity test specs with passing batches as another indicator that the “organization operates outside the framework of a robust quality system.”

Also cited was the firm’s lab procedure which “failed to establish proper retesting practices for OOS results.” The firm’s response to the

inspection findings, the letter notes, indicated that a combination of “inadequate SOPs, ineffective training and corporate audits failed to identify these deviations.”

The letter, in turn, asks Fresenius Kabi to provide an assessment of the adequacy of its lab operation, and “any new standards, controls, and improved oversight that you plan to implement.” The response needed further to address all lab and process-related equipment, “and any related software that may be affected by the lack of adequate controls to prevent data manipulation.”

FDA’s compliance office also requested that the firm’s investigation of its data handling problems include the identification of all data not described in product release/batch records and include a review of the audit trail. (see box above).

FDASIA Referenced on Obstructing Inspections

Another significant section of the warning letter addresses the steps that the Kalyani plant personnel took to obstruct the inspection.

Pointing out that during the inspection the firm “repeatedly delayed, denied, limited, or refused to provide information to the FDA investigators,” the letter reminds Fresenius Kabi that Section 7 of the FDA Safety and Innovation Act deems the products

FDA Summary of Corrective Action Needed at Kalyani Plant

You failed to establish an effective corporate and local system for managing quality which would include the appropriate organizational structure, procedures, processes and resources, as well as activities to ensure confidence that all APIs produced by your facility will meet the intended specifications for quality and purity.

We highly recommend that you hire an independent third party auditor, with experience in detecting data integrity problems, to assist you with the evaluation of your overall compliance with CGMP and assessing if data submitted to applications was impacted. If a third party is to be hired, please provide the FDA with a copy of their assessment. Also provide a copy of your assessment and investigation into the deficiencies presented in this letter describing the specific findings.

Please provide your corrective action plan that describes your commitment, procedures, actions, and controls to ensure data integrity. This plan should include the corrective actions implemented to ensure that all managers, supervisors, quality unit personnel and other staff are properly trained in detecting data integrity and manipulation. The investigation should provide detailed descriptions of other incidents where your quality unit failed to ensure proper testing of materials and include a retrospective review of all test results generated by your laboratory personnel. If other instances of non-existent, omitted, inaccurate, or unreliable test results are found, your investigation should assess the impact of these discrepancies on the quality of the APIs manufactured at your facility. Provide the documentation of specific training offered to all employees, including management, regarding the importance of following CGMP and ensuring that all required tests are performed, and data recorded completely and accurately.

In the warning letter to Fresnius Kabi on its Kalyani plant, FDA’s compliance office summarized its findings and outlined the extensive corrective action that it expected the firm to implement.

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adulterated when such obstruction takes place.

The explicit examples provided included:

● employee denials that the “trial” testing other than that reported on the official records was being performed and refusals to provide related information. Later the sample testing was admitted to relate to the blending of non-compliant batches with those meeting impurity specs.

● finding that raw data was being stored in personal files after being told that it was all in the central computer inaccessible to QC staff

● cleaning of rooms while access was denied

● attempting to hide manufacturing related records in a pocket so the investigator wouldn’t find it

● removing HPLC units and PCs from the facility to conceal data manipulations – an action, the letter notes, that had occurred in association with previous inspections and is “very worrisome.”

FDA asks for the company to provide a list of all manufacturing and lab equipment in the facility to produce and test products intended for the US market.

As at RPG, the compliance office “highly” recommended that a third party expert be brought in to assess the integrity problems and whether data submitted in applications was impacted, as part of the extensive CGMP corrective action program the agency wants to see implemented (see box above).

The warning letter asks Fresenius Kabi to contact FDA’s Drug Shortages Program if there is a potential supply impact from the remediation activity so that the agency can work with the firm in addressing it. The same request was made in the Wockhardt letter.

Pointing to the overall evidence of the weakness of the quality system at the facility, the letter includes a “strong” recommendation that corporate management “immediately undertake a comprehensive evaluation of global manufacturing operations to ensure compliance with CGMP regulations.”

As in the letters to RPG and Wockhardt, the compliance office warns Fresenius Kabi that until the corrective actions are confirmed, approvals of applications listing the API facility may be withheld and products manufactured there refused import.

Wockhardt Letter Continues Integrity Theme

The letter issued to Wockhardt in July provides further

insight into the eye-opening integrity lapses and efforts to cover them up that FDA has been finding on the Indian subcontinent.

In Wockhardt’s case the findings that the firm “withheld truthful information, and delayed and limited the inspection” are highlighted in the first paragraph of the letter and documented in detail in the six pages that follow.

As in RPG’s and Fresenius Kabi’s case, the letter also points to the inadequacy of the Wockhardt’s original response to the inspection findings and outlines an extensive course of action the company would have to follow to restore the agency’s trust.

The opening section of the Wockhardt letter lays out five examples of the company’s inspection obstructions. The examples involve:

● torn raw data records observed by the FDA investigator in a waste area that when asked for, were removed and only selectively delivered

● dumping the contents of unlabeled and partially labeled vials into a drainage sink after FDA asked for a description of their contents

● being initially mislead by the production head about his knowledge of the use of unofficial batch records forms for visual inspection results, who later acknowledged that he had directed the practice throughout the manufacturing facility

● the manufacturing VP not acknowledging, and directing FDA investigators away from, an aseptic filling line used for vial and prefilled syringe products for the US market

● not producing documentation involving the QC data package and raw data testing, in spite of multiple requests, until the last day of the inspection

Wockhardt Also Doing “Trial” QC

The second section of the letter deals with FDA’s finding of “unofficial batch records for approximately 75 batches of injectable finished drug products torn in half in a waste area.”

Unlike the “official” batch records which showed batches meeting specs, the unofficial records showed a significant percentage of batches with defects, including a variety of particles, sealing defects and volume variations that were not investigated in contradiction to the firm’s procedures.

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In its response to the inspection findings, the letter notes, Wockhardt confirmed that it was using its “unofficial” visual inspection to remove the defective units from the production line without appropriate documentation and investigation.

In the letter, the compliance office asks for “an independent and comprehensive evaluation of the extent of the deletion and destruction of records, a risk assessment regarding the potential impact on the quality of products, and a comprehensive corrective and preventive action plan.”

An overall quality system remediation plan should be submitted that describes the broader steps the company would take “to ensure direct corporate oversight over the quality and operations functions of this facility” and “the basic capability to prevent data manipulation and fraud.”

The third entry in the letter delves into the holes in the firm’s lab records, particularly regarding stability. As in the letters to RPG and Fresenius Kabi, FDA highlighted the practice of performing “trial” sample analysis prior to collecting the “official” analytical data and then not documenting or investigating failing data.

Related to this was the finding that the QC HPLC raw data

files could be deleted from the hard drive using the common PC login used by all analysts.

Citing the shortcomings in Wockhardt’s inspection response on the trial runs, the warning letter asks the company to evaluate all of its lab equipment and “any other process-related equipment that may be affected by the lack of adequate controls to prevent data manipulation.” In addition, FDA said, “address the root cause of your quality unit’s failure to control and detect the manipulation or alteration of laboratory documents, and describe actions to prevent recurrence.”

A fourth focus in the letter involves an analysis of a computer “crash” in a central lab computer and the firm’s inadequate efforts to determine and/or report on its impact.

A fifth area of concern was cited is the incomplete training records at the facility on “critical GMP activities,” and a sixth, the inadequate and poorly maintained washing and toilet facilities in working areas. The letter points out that inadequate cleaning and sanitary conditions were also noted during previous inspections.

Comprehensive Corrective Action Plan Required

At the conclusion of the letter, FDA summarizes the need

FDA’s Assignment for a Data Integrity Consultant at Wockhardt

● Identify any historical period(s) during which inaccurate data occurred at your facilities.

● Identify and interview your current employees who were employed prior to, during, or immediately after the relevant period to identify activities, systems, procedures, and management behaviors that may have resulted in or contributed to inaccurate data reporting.

● Identify former employees who departed prior to, during, or after the relevant period and make diligent efforts to interview them to determine whether they possess any relevant information regarding any inaccurate data reporting.

● Determine whether other evidence supports the information gathered during the interviews, and determine whether additional facilities were involved in or affected by inaccurate data reporting.

● Use organizational charts and SOPs to identify the specific managers in place when the inaccurate data reporting was occurring and determine the extent of top and middle management involvement in or awareness of data manipu-lation.

● Determine whether any individual managers identified in [the previous item] of this subparagraph are still in a posi-tion to influence data integrity with respect to CGMP requirements or the submission of applications; and establishing procedures to expand the internal review to any other facilities determine to be involved in or affected by the inac-curate data reporting.

The following are the tasks that the FDA warning letter requests Wockhardt to assign to an indepen-dent consultant with expertise in data integrity issues:

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for Wockhardt, like RPG and Fresenius Kabi, to provide a corrective action plan that describes its “commitment, procedures, actions and controls to ensure data integrity.”

FDA’s expectations for Wockhardt mirror those described in the Fresenius Kabi (see box on p. 4).

Wockhardt’s plan, the agency states, “should include the corrective actions implemented to ensure that all managers, supervisors, and quality unit personnel are properly trained in detecting data integrity and manipulation.”

The firm’s investigation, in turn, “should provide detailed descriptions of other incidents where your quality unit failed to ensure proper testing of materials and should include a retrospective review of all test results generated by your laboratory personnel. If other instances of non-existent, inaccurate, or unreliable test results are found, your investigation should assess the impact of these discrepancies on the quality of the drug products manufactured at your facility.” FDA also requests “the documentation of specific training offered to all employees regarding the importance of following CGMP and ensuring that all required tests are performed.”

Again, the compliance office calls for a third party auditor to be brought on board by Wockhardt, “with experience in detecting data integrity problems, to assist you with this evaluation and to assist with your overall compliance with CGMP.” The letter details what it wants the consultant to accomplish (see box on p. 6).

Culture of Fraud at Ranbaxy Revealed by Whistleblower

The types of data integrity issues reported by FDA in the recent Indian warning letters are similar to those found at Ranbaxy five years earlier that were brought to light by a former employee turned whistleblower. The consent decree reflected the warning letters that Ranbaxy received at its Dewas and Paonta Sahib facilities in 2008, which centered on data handling and falsification practices.

At the time of the consent decree that followed in 2011, the Ranbaxy announced that it had put aside $500 million to cover the potential costs of civil and criminal liability.

In May 2013, the generic drug manufacturer pleaded guilty to three felony counts of violating federal drug safety laws and four of making false statements to FDA. It acknowledged that it had failed to conduct proper safety and quality tests of several drugs manufactured at its Indian plants.

In a statement released after the guilty plea was entered, Ranbaxy noted that the settlement involved “conduct that occurred several years ago.” Also in the statement, Ranbaxy

CEO Arun Sawhney said “today’s announcement marks the resolution of this past issue.”

The company is paying $150 million in a criminal fines and forfeiture, with the remainder going to settle civil claims brought by the federal government and all 50 states. Dinesh Thakur, the former Ranbaxy executive who alerted FDA to the problems, will receive close to $49 million in compensation for his role as a whistleblower. The whistleblower in the case brought against GlaxoSmithKline regarding GMP problems and criminal activity at its Cidra, Puerto Rico site in the early 2000’s, which was settled in 2010, received the even larger sum of $96 million (see IPQ “Monthly Update” October 2010, p. 31).

Investigations by FDA beginning in 2008 revealed numerous problems with Ranbaxy’s manufacturing and testing at facilities in both India and the US, and data integrity problems at its India operations, including backdating of tests and submitting test data for which no test samples existed.

A widely-read Fortune article, “Dirty Medicine,” released a few days after Ranbaxy’s guilty plea, focused on allegations made by the whistleblower that highlighted the endemic nature of the firm’s quality and integrity problems and supported FDA’s inspection findings.

The article contains a detailed walk-through of the inside function, and dysfunction, at Ranbaxy during Thakur’s tenure there from 2002 to 2005, and continued infringements up through 2009. According to the article, Thakur said a Ranbaxy official told him that “the company culture was for management to dictate the results it wanted, and for those beneath to bend the process to achieve it.”

Thakur had begun internal investigations in August 2004 and, after leaving the company in 2005, contacted FDA.

“Dirty Medicine” reports that the violations by Ranbaxy went beyond altering data to the point of wholesale falsification in reports for over a hundred drugs, and notes that these infractions were conducted or acknowledged at all levels of the company. Also included are interviews with other former employees about the high degree of data fraud and a company culture that put product approvals above professional and personal integrity.

DOWNLOADS FROM THE STORY: FDA warning letters: • RPG Life Sciences • Fresenius Kabi • Wockhardt Fortune “Dirty Medicine” article

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MHRA’S GERALD HEDDELL ON THE ANATOMY OF A FACILITY WITH INTEGRITY PROBLEMS

The second of my two case studies [involves] an active substance manufacturer, again based here in the United States. It was an MHRA led inspection and…this was the sole site of supply for this particular active substance.

In this case, the company themselves held their hand up and, in fact, went in the first instance to the European Medi-cines Agency to advise that they had found significant GMP issues arising from data falsification in their API site.These issues only came to light when a new site director took office and changed the culture of that company. I will say a little more about the way in which that was achieved.

The same dilemma applied as [in the previous case study] – namely, that patients needed this product, and to withhold the product might cause more harm to public health.

A coordinated approach was taken across Europe. The European Committee for Human Medicinal Products [CHMP] was involved in that. The company submitted a corrective and preventative action plan and a quality improvement plan, and two batches of product were actually recalled voluntarily by the company.

A coordinated inspection took place, which the MHRA led. The inspection concentrated on areas outside those that were already addressed in the corrective and preventative action plan and the improvement plan, and found additional areas of concern – largely because the correction was based on the historical problem, rather than the future, and therefore [the inspection] found other areas.

The company is continuing to work through these improvement plans, and regular updates are being supplied. A re-inspection of the site, hopefully to give it an all clear, will follow a satisfactory completion of those improvements by the company and also [clearance] by a third party auditor that they have on site.

In this case, how did the company’s [problems] arise? Clearly the previous management managed through fear, and there was a significant discouragement of staff to actually report issues. The people working in the area near the is-sues were unable to report them. [There was] a very hierarchical structure which discouraged employees speaking up, and a mindset from the senior management that encouraged and really condoned poor GMP. The human resources division did not give any support for staff who wanted to speak up.

As a result of the change of a site director, the QA director, the production director, and the HR director were all dismissed. So it took a radical change of senior management in this company to actually turn things around and to provide an adequate response to the findings.

The learning point is a pretty obvious one I think, and it is a learning point that could be addressed as much as any-thing to CEOs of companies and to boards of companies. It does really move on from where [MedImmune VP Andy Skibo] was earlier. Have you got the right culture to make medicines? Not only are you making the right financial investments, which we saw from the previous case, but have you got the right culture? And if you haven’t, probably you shouldn’t be in the business. Is there too much dead wood and not enough fresh blood – stagnation or even pu-trification, if you like, in the case of this particular company?

Do you have the right systems in place that allow staff to escalate issues without fear of retribution? And how effec-tive is your corporate oversight? There is nothing that an external inspector should be able to find that the company themselves shouldn’t find through their own internal auditing program.

In a presentation on implementing the API provisions of the Falsified Medicines Directive (FMD) and other related European initiatives at an ISPE CGMP conference in Baltimore, Maryland in mid-June, UK Medicines and Healthcare products Regulatory Agency (MHRA) Inspection, Enforcement and Standards Division Director Gerald Heddell provided two case studies involving MHRA inspections in the US – one of which dealt with integrity issues at an API manufacturer. Heddell reviewed the inspection findings at that facility and drew some conclusions about how integrity problems relate to a firm’s quality culture and management.

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FDA Piloting Electronic FARs as Focus Intensifies on Defect Data Mining

FDA is piloting an electronic Field Alert Report (FAR) system that could help foster improved defect detection, prevention, and mitigation, and further empower the agency’s ability to understand where the industry shortfalls are and the particular firms that need heightened enforcement attention.

Defect reports are getting increased scrutiny from FDA and other regulatory authorities as an important indicator of where the primary GMP concerns lie and where the agencies should be focusing attention to better leverage their limited enforcement resources. The reports are one of several industry-wide metrics that FDA is considering using to compare the compliance positions of individual companies and help create a more flexible and rationalized review and inspection system (see IPQ “Monthly Update” June 2013).

FARs are required to be submitted when firms find potentially significant problems with products approved through new and abbreviated new drug applications (NDAs/ANDAs). Reports must be submitted to district FDA offices within three days of a problem being identified, unless the problem has been resolved during that time.

In an early May Federal Register (FR), FDA announced its intention to pilot the electronic FARs and invited industry volunteers to participate.

The annoucnement explains that the pilot is “intended to provide FDA with information to allow the agency to modernize the FAR submission and review pathway and permit integration with electronic archive filing systems.”

Under existing procedures, firms typically submit FARs via fax or scanned copy to their respective FDA district offices. The district offices triage the reports and provide them to CDER for additional review and analysis.

The FR notice points out that, under the pilot program, participants will be able to send an electronic FAR simultaneously to the selected FDA district office and to CDER’s Office of Compliance, “allowing for improved coordination within the agency as well as more efficient reporting by industry.”

The pilot program is open to all NDA and ANDA holders, and no additional software or licenses are required. The agency will also offer industry participants the opportunity to provide it with feedback regarding the use of the automated form. Firms are asked to contact the district office where they are located to sign up for the pilot, if interested.

Defect Data Mining Advances

How the agency is trying to better understand and utilize the FARs data – and the recall data with which it is associated – was explored by CDER Office of Manufacturing and Product Quality (OMPQ) Director Steven Lynn at the International GMP Conference cosponsored by the University of Georgia (UGA) and FDA in Athens, GA in mid-March and again at CGMP workshops sponsored by ISPE in June and the Food and Drug Law Institute (FDLI) in July.

“Quality defects serve as an early signal” of more serious issues, Lynn stressed at the UGA meeting. Agency tracking and trending of the defect data helps “inform our inspection program” and determine the state of control of manufacturing operations.

Defect data is also getting heightened attention in Europe, where agencies like the Irish Medicines Board (IMB) review the reports and bring the outcome to the attention of the inspections group to help it target areas to focus on during inspections.

Recent analyses by the IMB and FDA of their data on deviation reporting over the past few years indicate the prominence of packaging and labeling as a problem area in the pharmaceutical manufacturing arena (see IPQ “The News in Depth” July 15, 2013).

IMB found that over one-quarter of all deviations reported to the agency between 2008 and 2011 involved packaging and labeling. FDA’s analysis of FARs and recalls shows a similar prominence of packaging and labeling problems.

FDA Electronic FAR InitiativeAt the UGA conference in March, Lynn provided the fol-lowing comparison of the current FAR system with the proposed electronic system that the FDA is now piloting.

Current ProposedMul�ple formats and methods of delivery for incoming FARs from firms (PDF, and TIFFelectronic formats, postal mail, fax, email)

New form uses Adobe PDF and Extensible Markup Language (XML); new “submit” bu�on in form generates one e-mail

Firm reports sent to District Office and then to CDER

Allows simultaneous submission of FAR to ORA and CDER

No FAR numbering conven�ons

Unique iden�fica�on of each FAR

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FARs Data is Revealing

In his presentation at the Georgia conference, Lynn reviewed the previous five years of FDA FARs data in terms of : ● dosage forms ● domestic vs. foreign manufacturers ● NDA vs. ANDA products ● the top ten reporting firms in each category, and ● firms that file large numbers of reports vs. those that do not (Lynn’s complete remarks are provided below).

The compliance official pointed out the rough equivalence in the number of FARS submitted for generics vs. branded products, implying a similar level of quality between them.

He also highlighted the similarity in the number of FARs by dosage form in terms of filings in the US and overseas. Tablets made up the largest percentage in both cases – 40% and 36%, respectively – followed by sterile products, at 30% and 31%.

In analyzing the defect reports for sterile products, Lynn noted the wide divergence between the market share of injectable products (7%) and the number of FARs reports they generate (31%).

The vast majority of the injectable defects – 71% – were for drugs in solution, followed by saline/electrolytes at 16% and lyophilized products at 13%.

Regarding recalls for sterile injectables over the last five years, Lynn reported that issues with sterility assurance and discovery of particulates each accounted for 22% of the recalls. Impurities and degradation were responsible for 9%, whereas the “other” category – including issues such as discoloration, crystallization, failed pH specification, storage temperature excursions and documentation issues – were listed as causes of 47% of recalls.

Delving into the data on recalls for tablets, Lynn pointed to packaging and labeling as the most prominent reason.

About 30% of recalls of tablet products listed by FDA between 2008 and 2012 – 333 of 1112 – involved label mix-ups, incorrect packaging or incorrect product insert.

In 2012, labeling problems were the third leading cause of recalls overall, accounting for 48 products being called back from the market. Two other categories falling into the packaging/labeling arena, “presence of foreign tablets” and “defective containers,” were responsible for 18 and 12 recalls, respectively, in the FDA tally.

Company Numbers Vary Widely

In his analysis of FARS data, Lynn commented that the

number of FARs received from a company or sponsor is a “good indicator of general GMP compliance.” However, he cautioned that looking only at the number of quality defects by itself “may be misleading.”

The OMPQ official noted the wide discrepancy in the number of FARs being reported by individual firms.

Between 2008-2012, the ten firms that submitted the most reports accounted for 1289 – about 30% of the total filed during that timeframe. In turn, 781 of these 1289, well over half, were filed by only three firms.

“There are a lot more drug manufacturers out there than that,” Lynn pointed out. “So I do not know what is going on…. There are a handful of major manufacturers that account for a large number of the FARs that are coming in. Then there are similar size manufacturers or similar size product lines that have nothing, or a very limited number. This raises eyebrows, of course, and helps inform our inspection program moving forward.”

Electronic Pilot Targets Efficiencies

In a separate presentation at the UGA conference, Lynn delved into the electronic pilot and what the agency hopes to gain from more efficient communication between the industry and FDA.

Benefits of the Electronic FAR Ini�a�veTo Industry:

● U�lizes single submit mechanism; organiza�ons can email XML data and/or PDF files within a unified, readable e-mail● Enables organiza�ons to enter data efficiently and simplify data integra�on across the enterprise● Increases regulatory compliance – rapid transmission and follow-up from the agency● Reduces organiza�on’s transac�on �me significantly without need to print, cut-paste and copy paper files● Allows organiza�on to exchange files securely and electroni-cally with the agency ● Allows integra�on with electronic archive filing systems; no need to maintain both paper and electronic storage systems ● Encourages industry par�cipa�on in standardiza�on of data and repor�ng

To FDA:

● Intended to improve communica�ons with the industry ● Harmonizes Field Alert Repor�ng ● Facilitates ORA and CDER business process improvements● Supports GDUFA implementa�on● Provides rapid no�fica�on of emergent issues● Improves risk based alloca�on of ORA and CDER resources● Integrates product lifecycle informa�on

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whether participation will cause a disruption in field alert reporting ● the impact of the automated form on the reporting responsibilities of the applicant holder ● compliance with 21 CFR 314.81 ● notification of a firm’s FAR monitor at the agency regarding participation or discontinuation ● whether firms can opt out of the pilot after agreeing to participate, and ● how to access reporting forms.

Also in announcing the pilot, FDA pulled together a table that references and provides links to related announcements, regulations, forms, policies and guidance.

He explained that the pilot will be rolled out in phases. The first phase, announced in early May, is scheduled to run for eight months.

“Each phase will be rolled out incrementally to prevent disruption of business operations at ORA and CDER while allowing firms to participate in electronic reporting of FARs,” Lynn commented. The project is targeted for completion in about two years.

The OMPQ official noted that the initiative provides benefits to both the industry and the agency (see box on p. xx). “In the end, it seems like the US Postal Service will be the only ones who will not make out in the benefit column,” he quipped.

Along with the FR announcement, the agency released a Q&A regarding the pilot that addressed: ● the benefits of participating ● advantages over the current procedure ●

DOWNLOADS FROM THE STORY: • Q&A on the pilot • Federal Register Notice • Other related documents

OMPQ’s STEVEN LYNN ON QUALITY DEFECTS

In his presentation at the UGA International GMP Conference in March, OMPQ Director Steve Lynn dis-cussed the quality defect reports FDA receives for prescription drug products and related recalls. In re-viewing the data, Lynn compared and contrasted: ● defects received by application type ● reports received from US and overseas companies ● reports by dosage form ● sterile product defects vs. market share ● the number of reports received from the top ten reporting firms, and ● the wide variability in the numbers of defects reported by firms.

If you heard my presentation yesterday, I talked about Field Alert Reports and a new pilot program that is going to be kicking off here in the next month or so. This gives you two different areas of the Act and where it comes from in the CFR [21 CFR 314.81 – Other Postmarketing Reports; 21 CFR 314.98 (c) – Postmarketing Reports; FD&C Act, Sec. 505(k).]

Let me remind you folks who do not know what a Field Alert Report is – I hope you all do. It covers both NDAs and ANDA generics application holders. And foreign firms need to utilize a US agent within the States, and that agent must be registered to report FARs to the local district.

What is reported? This was mentioned yesterday. There are a handful of major manufacturers that account for a large number of the FARs that are coming in. Then there are similar size manufacturers or similar size product lines that have nothing, or a very limited number. This raises eyebrows, of course, and helps inform our inspection program moving forward.

If your firm has defects and you are not filing FARs, you are not complying with the law. If you have questions about whether or not to file a FAR, I would err on the side of caution and either send it in or, as an option, pick up the phone, call your local district, call someone in CDER – the district would be preferable – and get their opinion on that….

What is Reported?

• Applica�on holders are required to report to the FDA any incident that causes the distributed drug product or its labeling to be mistaken for, or applied to, another ar�cle – in other words, instances of adultera�on or misbranding.

• In addi�on, they must also report any:• Bacteriological contamina�on• Significant chemical, physical or other change• Product deteriora�on• Out-of-specifica�on result

• If the firm cannot invalidate problem within 3 days, a Field Alert must be reported

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If you cannot invalidate that problem within three days, you must file a report.

So let’s give an example – an out-of-spec result obtained during a stability testing or from ‘retains’ in appearance or particulates. If you cannot confirm the out-of-spec within three days, of course, you still report it. If the product is at expiry, you still need to report it. Remember: invalidate the problem within three days. If you cannot do that, you need to file.

So what does it mean to have a [complaint for a distributed product] that is ‘deemed significant?’ Go back to the previous slide where it describes what is reported: ● It is ‘distributed.’ ● It is a labeling problem. ● There is bacteriological, microbiological – virus, fungus – contamination, which we have unfortunately seen too much of. ● There is some type of significant chemical, physical or other change to the distributed product. ● There is some type of product deterioration ● There is an out-of-spec result for a distributed product.

About the receipt and processing of quality defects: You have a defect, you fill out your FAR, clear it through the firm, send it to your applicable district office. And then it goes on to our drug surveillance and data reporting branch in CDER’s Office of Compliance within my office, the Office of Manufacturing and Product Quality, where we have a team of pharmacists, doctors and compliance officers who triage, track, trend and report.

They enter their data into a database. FDA’s IT system is antiquated – we are actually using an Access database. And then the analysis from our FARs data is used to inform our inspection program, our operations and so forth, for enforcement opportunities.

Analysis by Application Type/Firm

To go into some numbers – here is a slide showing the number of FARs for the past several years. We are talking about NDAs and ANDAs. As you can see, a pretty close number…. Is the quality of innovator and generic drugs the same? I will let you be the judge. But it looks pretty close, according to defects at least.

Let’s look at quality defects from overseas firms, foreign sites. You can see the generics side of manufacturing is slightly higher than the innovator. Let’s dig into that a little bit more.

This shows the quality defects from the top 10 reporting firms. This is going back to what I said four or five slides ago. As you can see, overview across all of them, and of course we have removed all the names to protect the innocent. But if this does not exemplify the Pareto principle, I do not know what does. As you know, Vilfredo Pareto had the 80-20 principle – 20% of the issues are responsible for 80% of the problems.

Look at firms A, B and C, [and the disproportionate number of their filings.] And then going down you see the other drug manufacturers. So you go down to J, where it says 11. There are a lot more drug manufacturers out there than that. So I do not know what is going on. There are either no problems out there or people are not reporting. I will let you be the judge.

Defects from overseas firms by dosage form – back to foreign manufacturers. Tablet problems accounted for 36% of the reports coming from abroad. The next one after that is sterile problems – a close second at 31% – followed by capsules, at a miniscule 7%. So back to my good friend Vilfredo Pareto and his 80-20 principle. There is a lot of opportunity in those first three to figure out what is going on

Quality Defects by Applica�on Type 2008-2012

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AllOverseas

Quality Defects for Top Ten Reporting Firms 2008-2012

298 297

186

10796 87

79 78

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and fix the problem and mitigate a lot of defects, a lot of lost money and a lot of public health that is being put at risk.

Let’s go into the domestic side. It looks pretty much the same. So again tablet manufacturing problems are the leader at 40%, 4% higher than the foreign manufacturers. Also sterile comes in a close second, at 30%, 1% lower than abroad – pretty much the same. Then down to the orals at 8%. Tablets and steriles are 70% of the total dosage form problems. I hope you agree with me that we need to work together and find the solutions. We need to get there, of course.

I also think that it should be pointed out that we cannot forget about the other dosage forms. As Pareto says, you try to concentrate on the 20% and you fix 80% of the problems. But if don’t look at all 100%, once we fix the 20% we are going to have problems coming from the other dosage forms. So you have to look across your entire system of products. But there is an opportunity definitely with the 20%.

Analysis by Product/Defect Type

Let’s go into some examples of the tablet quality defects. Now this is both from the foreign and domestic side. This is over the last five years. We have had 1,112 recalls. The number one is labeling mixups. There are 222 of them, or 20% of the total recalls. Subpotency comes in at number two – not enough active in the ingredient or something – at 108, or 10% of the total. Impurities and degradation is next at 93, or 8% of the total.

Look down at the bottom where it goes over ‘other defects’—the other category which is a catch-all category if you want to call it that. There are 461 of those. That accounts for 41% of the recalls. So again going back up, that is a list of such things as presence of foreign substances, which we have seen way too much over the past couple of years, stability data not supporting the expiration date, chemical contamination, all the way down to labeling and incorrect/missing lot numbers or expiration dates. So back to Vilfredo again – Mr. Pareto – the top three present an opportunity to fix the large percentage of defects in all the operations.

Look at steriles – market share versus percent of defects. You would think the majority would rule in this case but it is not true. Sterile manufacturing problems have been a major contributor to drug shortages the past few years as we all know. We talked about that a little bit yesterday. As I mentioned, I am happy to see our drug shortage staff, working with manufacturers and others at CDER and ORA, have been able to work with various industry constituents to mitigate more shortages this year than last year – or year and a half – but we are still having shortages, unfortunately.

I still challenge all of our quality compatriots in this room with their operations brethren and their senior management to put in fixes of this nagging problem. It keeps coming up and we are putting patients at risk. As I like to tell folks, you never know when you are going to be ill and lying in that hospital bed, and they are going to put that IV in your arm.

Examples of Tablet Quality Defects and Recalls 2008-2012

CGMP devia�ons - 1112 recalls– Label mix-up - 222 recalls– Sub-potent drugs - 108 recalls– Impuri�es/degrada�on products - 93 recalls– Failed Tablet Dissolu�on requirements - 84 recalls– Wrong packaging - 72 recalls– Incorrect/Missing Package Insert - 39 recalls– Penicillin cross contamina�on - 33 recalls– Other Defects Reported: (461 recalls)

• Presence of foreign substances• Stability data does not support expira�on date• Chemical contamina�on• Contracep�ve pills out of sequence• Discolora�on• Tablet weight/thickness/separa�on, blend uniformity• Labeling• Incorrect/Missing Lot No. or Expira�on date

Perc

ent o

f Def

ects

Rep

orte

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Defects by Dosage Form, 2008-2012 US vs Overseas

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Tablet Sterile Capsule

US% vs Total USOverseas% vs Total Overseas

Sterile Injectables Market Share Vs Percent Defects

93%

Market Share - InjectablesMarket Share - Other Dosage Forms

93%

7%

FARS - Other Dosage FormsFARS - Injectables

31%

69%

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Let’s go into the breakdown of defects by the type of injectable. So if you look, drug in solution is number one at 71%, down to saline or electrolyte solution at 16%, followed by lyophilized product at 13%. So drug in solution [represent] a huge opportunity to fix.

Quality defects and recalls for sterile injectables for the last five years: Sterility assurance and particulates are the frontrunners with 22% of the recalls. And again down at the bottom, the other category, the catch-all hodgepodge, is around 47%. But lack of sterility assurance is the top one and then talking about visible particulates, down to impurities and degradation, are definitely issues that we need to look at.

Injectable defects across the last five years: You will see it spiked in 2011 with 498. This was the height of the drug shortage epidemic. And this year, thankfully, it has gone back down. But if you look at the 340, it is still higher than the first three years, 2008 through 2010. So there are still problems. There are still opportunities to protect the public health of course.

Sterile injectable defects from the top 10 reporting firms. Again, look at the numbers across, all the way down to J with 30. There are a lot more sterile injectable manufacturers out there than ten. 271 from one firm. Again, we talked about that yesterday. Is it over-reporting? Is it just reporting everything? What is it? I can definitely guarantee they have problems, but…they are doing what they need to do to get those reports in.

Let’s look at all dosage forms recalled versus the sterile injectables recalled. To drive home my previous point a little bit further – sterile injectables, as you can see, are vastly higher than all other dosage forms being recalled [compared to their market share]. And we

have a lot of work to do to fix this problem.

Breakdown of Injectable Defects by Type 2008-2012

• Lack of assurance of sterility - (22% of recalls)– Bacterial endotoxin specifica�on not met– Container defects; cracks, breaks, leaks– Ques�onable container/closure sterility

• Presence of visual par�cles - (22%)

• Presence of impurity/degrada�on products - (9%)– OOS for related substance impurity specifica�on at 8, 12, 18

months– Stability failure at 18 months

• Other Causes - (47%)– Crystalliza�on, Discolora�on, Failed pH specifica�on, Storage

temperature incursions, Incomplete documenta�on, Absence of stability indica�ng methods

Breakdown of Defects by Type of Injectable 2008-2012

16%

Injectable - Drug in Solu�onInjectable - Saline/ElectrolytesInjectable - Drug Lyophilized

71%13%

Injectables: Defects for 2008-2012

121169

498

340

2008 2009 2010 2011 20120

100

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400

500

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Sterile Injectables: DefectsTop Ten Repor�ng Firms 2008-2012

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82 80 72 6554 52

271

109

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Sterile Injectables Recalled vs. All Dosage Forms 2008-2012

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2007 2008 2009 2010 2011 2012

16% 12%22% 19%

18% 21%

INJECTABLE

ALL DOSAGE FORMS

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Key Messages

Quality defects serve as an early signal. We talked about this yesterday: detect it early, fix it early, save yourself problems, protect the public health – as simple as that. Look across your entire system, your state of control, make sure everything is in control and you produce a fit-for-use quality product.

Trend analysis is a valuable tool for post-marketing surveillance for quality performance of a distributed product, class of products, firms, regions, etc. Trending at regular intervals (you figure it out, monthly, quarterly, yearly – I would say quarterly or monthly is probably better, because if you do annually, you are not going to fix something ahead of time) does and can provide useful additional knowledge regarding the quality of your drugs. Early detection is best, of course. If you can fix it early, save yourself money and protect the public health.

The number of FARs received from a company or sponsor is usually a good indicator of general GMP compliance. Quality defects can take many forms, such as products with missing labels, sub-potent products, particulates and so forth.

However, just the number of quality defects by itself may be misleading, as there are several variables.

There can be under-reporting. We have a concern about that. I can say that is definitely true. There could also be over-reporting.

Looking at the number of firms producing drugs vs. the number submitting defects into the office – a small number account for the largest number of FARs reports coming in.

Taking a holistic approach across your entire system from manufacturing through distribution – across your whole supply chain – is essential to making a comprehensive assessment of quality. Look across the manufacturing operations that you have under your control. Look at all your outsourced operations – contract manufacturing, API manufacturing, you name it – to make sure everybody else is in control.

Ultimately, at the end of the day, if your product is the one that has a problem, and you have ten different contractors that feed into that product, you are responsible. It is your responsibility to protect that product to be sure the public gets what it deserves.

In conclusion, I will leave you with a couple of questions: ● Is it feasible to establish an acceptable level of quality defects for a firm, for a certain dosage form, or for a product itself? Think about it. I will not answer that question for you, but I want to put it to you. ● Is it possible to have globally-harmonized quality ratings for firms – a specific rating for a firm, a scorecard for manufacturers?

These are two key questions we are struggling with right now at the agency. We are looking at trying to figure out better surveillance activities, better ways to target our limited resources going forward.

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EUROPEFMD Implementation in Europe Drives Better API Sourcing Knowledge and Interagency CommunicationsImplementation of Europe’s Falsified Medicines Directive (FMD) has shed important light on what the active pharmaceutical ingredient (API) part of the global pharmaceutical supply chain actually looks like and has led to enhanced communication between the countries that participate in it.

One of the four basic components of the FMD involves increased assurance that all APIs being imported into Europe have been manufactured under EU-level GMPs. The directive also strengthens the EU requirements for: ● product identification and tracking ● good distribution practice, and ● Internet pharmacies.

Coming into force on July 2 was the directive’s requirement that API manufacturers must get written confirmation from their domestic regulatory authority that they are in compliance with EU GMPs before the EU will grant entry of their product, if their country has not been formally recognized as having an equivalent GMP oversight system (see IPQ “Monthly Update” May 2011, pp. 27-35). A third possibility, intended for use when medically necessary products are involved and the previous two pathways are not available, is for an API plant to undergo an inspection by an EU authority and be issued a GMP certificate that allows importation.

The FMD API import provision has led the EMA, in conjunction with the member states, to carefully map out where all of its APIs are coming from and has intensified the dialogue between EU regulators and authorities in countries with firms that manufacture APIs intended to be exported into Europe.

At a conference on the “Current and Emerging EU Regulations and Inspection Trends” co-sponsored by PDA and the Irish Medicines Board (IMB) in Dublin, Ireland, in July, EMA Senior Scientific Administrator Riccardo Luigetti highlighted the impact that the FMD implementation process is having on inter-agency communications and cooperation.

The FMD “has increased dialogue and cooperation between the EU and key third countries from a commercial point of view,” he commented. “The European Commission, the member states, and EMA are talking much more with the third country authorities.”

Implementation of the FMD, Luigetti emphasized, “is also facilitating the process for third countries to become part of the global regulatory system. The EU has led this process. The aim is to bring them to our level in the future.”

Supply Chain Vulnerabilities Mapped

At a conference on “Redefining the ‘C’ in CGMP” cosponsored by ISPE and FDA in June in Baltimore, Maryland, UK Medicines and Healthcare Regulatory Authority (MHRA) Inspections, Enforcement and Standards Division Director Gerald Heddell discussed the API supply chain “mapping exercise” that MHRA and EMA conducted and how the results are being used to understand the locations of the suppliers and the vulnerability of the supply chain for active substances being imported.

MHRA, he noted, mapped the APIs that are authorized by individual member states – 80% of the total. EMA focused on the remainder that are centrally authorized. Heddell presented the combined data.

The effort identified about 1,600 factories in 41 “third countries” – i.e., countries outside the EU – that are licensed to supply active substances to Europe. The majority of the sites are located in India (496 – 31%), China (438 – 28%), the US (192 – 12%), Japan (108 – 7%), and Switzerland (67 – 4%) (see box below).

The data was broken down further to reveal how many sites in each country would clear the import criteria based on: ● written confirmation ● being located in an approved third country, or ● having a

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GMP certificate.

93 API sites (about 6%) were identified across 22 countries that could not meet any of the three options for import approval. Over half of the 93 sites are located in China (33), Brazil (15), and Argentina (9).

Since Mexico, Israel, Canada, Taiwan and Turkey have formally agreed to supply written confirmation of GMP compliance, the sites in those countries are not included among the 93. The list does include sites from Brazil, Argentina, Malaysia, Chile and Thailand, which have not yet committed to supplying written confirmations. Sites from these latter countries that have EU-supplied GMP certificates do not appear on the list.

Of particular note is that only the US, Japan, Switzerland and Australia – accounting for just 24% of the APIs imported into Europe – have cleared the EU approval process to be recognized as third country suppliers with equivalent API GMP regulatory oversight.

The US is the latest to be approved – added to the list on June 26 just under the wire of the July 2 implementation date. Israel, Singapore, Brazil and New Zealand have also applied for third country recognition, but have not yet been approved. New Zealand applied in June (EMA’s current table on applicants/approvals is provided below).

Other countries that have indicated interest in applying but have not yet done so include: ● South Korea ● South Africa ● Ukraine ● Mexico ● Taiwan, and ● Argentina. The applicants and those interested in applying have expressed their intent to provide written confirmations during the interim period.

Heddell explained that different member states may have somewhat different import requirements

as well as variance in their API supply chains. He noted that an assessment was performed by the MHRA similar to that done for the EU member states in aggregate, which indicated that nine factories supplying the UK were at risk of noncompliance.

Some of the key questions that MHRA is wrestling with, Heddell pointed out, are: ● “What are we going to do about those nine factories? ● What if some of the countries that have offered to provide written confirmations do not? ● What if they are not able to because they haven’t visited the site in question?”

Potential Drug Shortages Addressed

Due in part to the relatively low percentage of API manufacturers that are supplying Europe from approved third countries, a primary concern of the European authorities including MHRA is anticipating and heading off drug shortages that may result from APIs that do not meet the new import criteria.

EU’s Heads of Medicines Agency (HMA) published a decision tree in June intended to assist importers and other supply chain participants that may have difficulties in obtaining written confirmations.

The decision tree details steps that can help avoid problems at the point of importation, or later in the supply chain, for an API that has not come from a designated third country and does not have a written confirmation from a competent authority (link provided at the end of the story). The process described in the decision tree is predicated on the importer having already applied for a written confirmation of GMP compliance in the exporting country.

Alternatively, the firm can apply for a waiver from the competent authority in the EU country that it intends to export to. The waiver requires that the API is for a product that is medically necessary, and that the firm has a GMP certificate issued within the previous three years following an inspection by a European authority. In these cases, the API will be quarantined until the waiver has been cleared.

The process also considers whether any other recognized authorities – for example, FDA, WHO, or EDQM – have documented GMP compliance of the site.

Heddell explained that the EU procedures for inspection of API manufacturers make it unlikely that many of the applying firms will meet the criterion of having already been inspected and issued a GMP certificate.

“Unlike in the US,” he commented, “in Europe there has been no mandatory instructions, no legal reason to

Status of Countries Applying for “Third Country” Designa�on for API Import into EU as of July 2

Country Date of request Status, Date of publica�on in the Official Journal of the European Union

Switzerland April 2012 Approved, November 2012

Israel May 2012 Contacts ongoing.Australia September 2012 Approved, April 2013Singapore September 2012 No lis�ng for the moment (the relevant

Singapore legisla�on provides for a non-mandatory GMP cer�fica�on scheme). Contacts ongoing. In the mean�me, Singapore issues wri�en confirma�on.

Brazil October 2012 Equivalence assessment ongoingJapan December 2012 Approved, June 2013U.S January 2013 Approved, June 2013

ZealandJune 2013 Assessment ongoingNew

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routinely inspect active substance manufacturers.” APIinspections have taken place, but “largely on a ‘for cause’basis rather than on a routine basis.” As such, the Europeanauthorities are not resourced to handle a large number ofAPI inspections.

EMA’s Luigetti commented at the PDA conference in Dublinthat shortages in the EU of essential medicines due to theFMD are “unlikely,” but that there could be shortages ofmedicines “that, from a public health point of view, are notconsidered essential by competent authorities.”

India and China Pose Special Challenges

The top two API suppliers to the EU – India and China – donot have GMPs directly equivalent to the EU, but accountfor almost 60% of imported APIs. Neither has appliedfor “third country” designation, instead choosing to issueindividual “written con rmations” of GMP compliance fortheir domestic rms.

In China, API rms that produce for export only areconsidered chemical plants by China’s CFDA and are notinspected. Those plants will not be eligible for the writtencon rmations. The EU effort identi ed 33 such plants thatwill need to be inspected by European authorities prior toshipping API into the EU.

India’s Central Drug Standards ControlOrganization (CDSCO) – the governmental bodythat will oversee the quality of APIs shipped toEurope – released documents earlier this yeardetailing how Indian API manufacturers canobtain a written con rmation of quality that willbe needed to ship their products to the EU (see IPQ“Updates in Brief” February 18, 2013).

The documents include administrative procedures to befollowed by API manufacturers and by CDSCO for issuingthe certi cation, and explain that the measurement standardwill be ICH Q7 or WHO GMPs. However, one of thedocuments – a checklist – intended to be used to measurecompliance, does not address, or inadequately addresses,many fundamental aspects of Q7.

Also of note is the lack in any of the published documentsof provisions to ensure that Indian API plants are “subjectto regular and strict controls and effective enforcement ofGMP, including inspections” as required by the FMD.

Additionally, the “Indian Drugs and Cosmetics Act andRules” does not have a provision for publication of guidancedocuments, only ways to amend the law itself. As such, thedocuments are not legally binding and CDSCO’s authorityto issue meaningful, acceptable certi cations based on themremains unclear.

Heightening the concerns about APIs sourcedabroad is a spate of FDA warning letters to bothAPI and nished dosage manufacturers that revealserious data integrity concerns. India has been aparticular target of FDA attention in this regard

(see story on p. 2).

A warning letter sent at the end of May to RPG LifeSciences, located in Mumbai, was followed by letters in Julyto Germany-based Fresenius Kabi, regarding its facility inWest Bengal, and to Wockhardt, regarding its headquarter’splant in Aurangabad, that encompass a nexus of issuesaround the integrity of records, procedures and interactionswith FDA investigators.

The three warning letters, in turn, follow in the wake ofthe high-pro le revelations from FDA’s investigation, inconjunction with a whistleblower, of the integrity problemsat Ranbaxy plants in India. The revelations resulted in amajor consent decree in January 2012 and have continued togarner media attention as more information has surfaced.

MHRA Instituting a Warning Letter Approach

The FMD is directed at assuring that APIs imported intoEurope are made with EU-level GMPs in place. Thatassurance, in turn, will rest on improved communicationchannels between agencies and manufacturers – andbetween agencies – about inspection ndings, along withfurther harmonization of inspection and GMP standardsthrough international mechanisms like ICH and PIC/S.

Sensitive to this need for more inspection and compliancetransparency, and wanting to improve the risk managementcomponent of its inspection program, MHRA is taking stepsto better communicate the GMP de ciencies it is nding.

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INSIDE THE GLOBAL REGULATORY DIALOGUE™

The challenge, Heddell explained at the ISPE/FDA CGMPconference in June, is determining what to do “aboutcompanies that I would describe as ‘walking a tightrope.’They do just about enough to remain compliant. Buteverybody within a regulator environment knows who theyare, and they know that at any point they might fall off thattightrope and things will go wrong. What do you do withsuch companies?”

One step MHRA has taken is to “gather more informationon the vulnerabilities of companies, particularly if they areengaged in producing essential medicines where there areno choices.” Similarly, FDA is exploring the use of metricsto help inform both its inspection program and to potentiallyprovide regulatory exibility in the application process (seeIPQ “Monthly Update” June 2013, pp. 12-20).

Heddell said that his agency is also introducing “anescalation process – the equivalent of a warningletter type approach – which would be followed byvery much closer monitoring of the company.”

The escalation process will include a step that informs the rm that formal action may be forthcoming. “This is beforewe have actually taken formal action. This is before the

company has actually really gone over that borderline, butis walking on it.” The communications will also provide the rm more information “that will allow them to manage thesituation.”

The MHRA of cial noted that his agency already publishessummaries of inspection ndings, but would like to do moreto help companies understand the risks that they are takingand have closer communication with those companies.

“So the secret, I think, to success, can never be regulatorssaying what needs to be done,” he emphasized. “And it cannever be companies thinking that they can somehow pullthe wool over the regulator’s eyes.”

Heddell maintained that the key is companies and regulatorsworking together and recognizing the shared responsibilityfor safe and effective medicines. “Only as we collectivelydischarge that responsibility do we really look after theinterests of our patients.”

During the Q&A after his presentation, theUK regulator was asked about the timing ofthe compliance improvement program beingundertaken by MHRA and the scope of the warningletter-like program.

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EMA ON IMPORTED ACTIVE SUBSTANCES

DOWNLOADS FROM THE STORY:

• HMA API import guide and decision tree • EU 2013 GDP guideline revision

On its website on July 2 – the day the import provisions went into effect – EMA published an updateon the API section of the FMD. The agency addressed: ● what is required for written confirmations toguarantee GMP standards ● the list of countries that have applied for equivalence determination andthe status of the applications ● the waiver for imported APIs that cross-references a separate guidanceand decision tree published in June, and ● a description of the goals of the FMD as a whole.

Falsified Medicines Directive: Imported Active Substances Need WrittenConfirmation to Guarantee GMP Standards

From 2 July 2013, all active substances manufactured outside of the European Union (EU) and imported into the EUmust be accompanied by a written confirmation from the competent authority of the exporting country which confirmsthat the standards of good manufacturing practice (GMP) and control of the manufacturing plant are equivalent tothose in the EU.

These requirements constitute one of the main areas of change of the new European falsified medicines directivewhich came into force in January 2013. They provide a clear legal basis for the concept of international cooperation onactive substances (also known as active pharmaceutical ingredients or APIs) which is based on sharing responsibilitieswith local regulators.

The written confirmation is required per manufacturing site and per active substance and should provide the followingassurances:

● standards of GMP applicable at the plant are at least equivalent to those in force in the EU;

● the plant is subject to regular and strict controls and effective enforcement of GMP, including inspections;

● information on findings relating to non-compliance is supplied by the exporting third country without delay to theauthorities in the importing country in the EU.

The duration of validity of the written confirmation is established by the exporting non-EU country.

These new requirements reinforce the need for pharmaceutical companies to ensure that the activesubstance manufacturers they are working with are registered with their respective local authorities and subjectto adequate regulatory oversight, no matter where in the world they are located. Marketing authorization holdersand applicants should always bear this in mind when selecting active substance suppliers to avoid future supplyproblems.

Heddell characterized the use of compliance information totarget inspection resources as “a progressive thing.” Theagency is beginning by putting more effort into gatheringdata on “the companies that we know are likely to causeproblems in the future. That is happening now.”

Asked whether the warning letter-like approach is beingconsidered by EMA or other member states, Heddell repliedthat only MHRA is adopting it at this time, but that overtime other agencies may follow suit.

Changes to GDPs Reviewed

Along with his discussion at the ISPE/FDA meeting of theEU and MHRA efforts regarding the importation of APIsunder the FMD, potential drug shortages, and MHRA’s

compliance escalation process, Heddell provided an updateon the revision to the EMA good distribution practices(GDPs) guideline that was published in March and becomeseffective in September.

He noted that the revision was needed to update the existing19-year-old GDP guideline to better re ect 21st centurysupply chains, adding that the revised guideline covers“areas that have never previously been required or expectedof UK wholesalers” (see box on p. 19).

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List of Equivalent Countries

The directive foresees that exporting countries with a regulatory framework equivalent to that of the EU will not needto issue written confirmations. Following a request from a non-EU country, the European Commission, together withGMP experts from Member States and with the support of the EMA, will assess the regulatory framework of therequesters and if the assessment if positive, the county will be listed as an ‘equivalent country’.

Four countries have been listed so far by the European Commission: Australia, Japan, Switzerland and the UnitedStates.

An equivalence assessment is ongoing for Brazil. Israel and Singapore have requested to be listed as an ‘equivalentcountry’. The European Commission maintains a webpage on quality of medicines and GMP detailing the status ofthe requests received.

Inspections Carried Out in Exceptional Cases

In order to avoid the risk of shortages of medicines if the required written confirmation cannot be obtained, the directiveprovides for a waiver from the written confirmation in exceptional circumstances. The waiver can be used where aninspection by an authority of the European Economic Area has been carried out with a positive outcome and the issueof a GMP certificate.

With around 30% of centrally authorized medicines using active substances that are sourced from third countries,the Agency has performed a risk analysis for centrally authorized products to identify priorities for inspections. Themethodology was shared with Member States allowing them to apply a similar approach to nationally authorizedmedicines. The Agency is constantly monitoring the situation in liaison with Member States in order to coordinate thisactivity.

In the meantime, guidance for importers and National Authorities has been prepared to deal with cases where activesubstances arrive in the EEA without the necessary written confirmation. This has been prepared to facilitate aharmonized approach over the coming weeks.

About the Falsified Medicines Directive

In July 2011, the EU strengthened the protection of patients and consumers by adopting a new Directive on falsifiedmedicines for human use.

The Directive aims to strengthen the supervision of the supply chain of medicinal products and active substances, inorder to avoid falsified medicines entering the EU market.

In addition to the requirements related to active substances described above, the directive also foresees:

● the introduction of unique identifiers printed or attached to every single pack of medicines subject to prescriptionand other medicines at risk of being falsified;

● the construction of a unique database containing information on both GMP and Good Distribution Practices(GDP); EudraGMDP was launched in April 2013;

● the introduction of an obligatory logo that will be placed on the websites of legally operating onlinepharmacies.

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A clear distinction between the release of a batch and itscerti cation by the Quali ed Person (QP), directions for whatresponsibilities the QP can share and how, and a templatefor use by a QP to sign off on a subset of manufacturing stepsare among the signi cant changes EMA has incorporatedinto a revision of its Annex 16, which was released for publiccomment in early July.

The EMA is providing a four-month consultation period –one month longer than is typical – to factor in the Europeansummer holiday period. Comments are due by November5.

At a conference on the “Current and Emerging EURegulations and Inspection Trends” co-sponsoredby PDA and the Irish Medicines Board (IMB) inDublin in July, IMB GMP Manager Paul Sextonprovided insights on the changes to the annexand why they were put in place. Sexton has beenparticipating in the revision effort, which is beingshepherded by EMA’s Inspector’s Working Group.

Some of the key drivers for the revision, Sexton explained,include: ● the globalization of the pharmaceutical supplychain, which is “putting more distance between QPs andthe manufacturing operations for which they are ultimatelyresponsible” ● the introduction of new quality controlstrategies such as real-time release ● the implications ofthe falsi ed medicines directive (FMD) and the re ningof the GDPs in Europe ● the principles embedded in ICHQ8-10 ● a new manufacturing and import authorization(MIA) interpretation document, and ● differences betweenmember states in interpreting the existing Annex 16 .

Need for Annex Revision Clear

The need to revise Annex 16 in light of the changes that haveoccurred in the pharma industry since its introduction in2002 and the implications of those changes on the QP’s rolewas explored at a PDA/EMA conference in London in May2011 (see IPQ “Monthly Update” June 2011, pp. 9-13).

At the conference, Finnish National Agencyfor Medicines (FIMEA) Senior PharmaceuticalInspector Anne Junttonen, who is the InspectorsWorking Group (IWG) lead on the Annex 16review, previewed a concept paper on the revisionthat was in preparation and requested input fromthe attendees.

Input from both industry and regulators, she said, wasimportant to help the group in its consideration of how

the role of the QP should be rede ned in view of theQbD regulatory framework and an increasingly complexmanufacturing/supply chain.

An informal meeting between some of the key industrystakeholders and top EU regulators held immediatelyfollowing the conference provided the initial opportunityfor the input and dialogue to take place (see IPQ “MonthlyUpdate” June 2011, pp. 14-19).

The concept paper was released for a three-month publicconsultation in October 2011.

Revision Drives Supply Chain Transparency

The challenges that the revision of Annex 16 presented andthe IWG’s progress in meeting them were further discussedby Junttonen at a December 2012 PDA/EMA conferencein Cascais, Portugal (see IPQ “Monthly Update) Jan./Feb.2013, pp. 43-47).

The concept paper drew comments from 22 stakeholders.Junttonnen pointed out that they were “all over the board,”with some urging a focus on principles rather than detailsand others requesting more speci c guidance on handlingspeci c situations. Other comments requested changes thatwere not in accord with the directive to which the Annexmust adhere.

The comments prompted the IWG to take a fresh look atwhat was needed to be accomplished in the revision andto reach out to industry associations to get help mappingsupply chains and the various export, import and re-importscenarios to ensure that the annex revision would properlyre ected the real-life scenarios a QP might encounter.

The mapping needs associated with the annex revisiondovetailed with an effort by EMA to better understand APIsupply chains in advance of implementation in July of itsAPI import provisions (see the story on p. 16). The resulthas been a signi cant advance on the transparency of theglobal pharma supply chain.

QP as Surrogate Regulator

At the December conference in Portugal, Junttonencommented on the high-level role of the QP and how itintersected with that of agency inspectors in assuring drugquality. In some ways, the QP serves as a regulator “manin the plant.”

The role of inspectors, Junttonen explained, is to ensurethat when companies are pursuing making pro ts for

Revision of EU Annex 16 Clarifi es QP Responsibilities in the Face of anIncreasingly Complex Supply Chain

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INSIDE THE GLOBAL REGULATORY DIALOGUE™

shareholders “they are not causing any risk to the patients.They are not doing things that might reduce the trust ofpatients to the legally supplied medicines.” The regulatoralso looks across multiple companies for non-compliancetrends.

The QP, she maintained, is “doing practically the samework,” but is looking at the legal requirements on a batch-by-batch basis.

While QPs in the EU are not necessarily the formalhead of the quality system, they are the fi nal arbiterof the quality risk management process in makingthe determination that a batch is suitable formarketing.

At the PDA/IMB conference in July, IMB’s Sexton commen-ted that the QP “tends to be a person that the regulator goesto, because they really are a person that is deemed to haveknowledge of the manufacturing process, and they are aresponsible individual that has de ned responsibilities formanufacturing activities.”

They are often a key contact person in relation toinvestigations of complaints, quality defects or recalls, henoted. Although the marketing authorization holder “iscertainly the rst point of contact in a recall situation,” interms of trying to get the details of investigations, “the QPwill often be the key contact.”

Batch Release vs. Certification

Commenting on the batch release vs. certi cation distinction,Sexton noted that it is not a new topic, but one that “we asregulators are being more careful about in choosing ourwords. I certainly have used the term ‘batch release’ whenI meant ‘batch certi cation.’ I suppose we are getting a bitmore pedantic in Annex 16 on the two processes.”

He explained that the certifi cation by the QP shouldtake place at the site that is named in the marketingauthorization.

“Ironically,” Sexton commented, that site is referred to ina marketing authorization as the “site of batch release,”which “is a bit of a con ict in terminology. What you mightunderstand as being the site of batch release, we wouldunderstand from the marketing authorization as being thesite of certi cation.” He commented that harmonization ofterminology between the marketing authorization and theEMA “notice to applicants” is something that will need tobe addressed in the future.

The revision of Annex 16 contains a de nition of “releaseprocess” and a section on the process, which outlines thechecking of manufacture and testing in accordance with

de ned release procedures, the certi cation step by the QP,and the assigning of the release status to the batch.

Also specifi ed in Annex 16 is that the QP isresponsible for assuring that the manufacturer’sauthorization provides for batch certifi cation as amanufacturing activity.

Sexton noted that a Manufacturing and ImportingAuthorization (MIA) “interpretation document” will beavailable “soon” and will provide an explanation of each ofthe batch certi cation related activities within a Europeanpharma rm. Following the guide will mean that “every timeany site is authorized for a batch certi cation, it should beclearly identi able from the manufacturing authorization.”

QPs Can Share Responsibilities

Signi cant adjustments were made to Annex 16 around theQP’s delegation of tasks and how the QP can have assurancethat all operations at all parties in the supply chain havebeen conducted in accordance with GMPs and both country-speci c and European laws and guidelines.

The revision addresses the common scenario thatoccurs when part of a manufacturing step is carriedout either at a different site or by a different fi rm,and how the QP responsible for that portion of themanufacturing process can assure compliance ofthat part of the overall process.

It speci es that a QP at a site that is carrying out partialmanufacture must con rm compliance of that piece of themanufacturing process.

In turn, the QP that performs the nal sign-off on the batchat the site named in the marketing authorization mayshare responsibility with QPs con rming earlier steps.Commenting that this model is not new, Sexton explainedthat it is more clearly de ned in the annex revision.

“QPs rely on other people all the time,” he pointed out. “Buta QP being able to share responsibility with another QP issomething that makes it different than just saying you relyon somebody.”

The Annex 16 revision includes a template for useby the QP at a site of partial manufacture to confi rmcompliance of that portion of the process with: ●GMPs ● the terms of the marketing authorizationfor the destination country, and ● the technicalagreement with the site that will certify the fi nalproduct.

The requirement for a technical agreement between the siteof partial manufacture and the site of nal certi cation is

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new, as is the emphasis on meeting marketing authorizationrequirements for the country where the product will besold.

“In con rming compliance with the marketing authorization,if the QP is doing a con rmation of a partial manufacturingstep, then...we would expect that they have the details ofthe marketing authorization available at the site,” Sextonstressed.

A similar arrangement between QPs within a manufacturingsite that has a number of QPs sharing responsibilities is alsodescribed, and should be governed by a company procedurerather than a technical agreement. “If there is division ofresponsibilities, then this needs to be de ned” independentof where the QPs are located or whether they work for thesame rm, he emphasized.

Additional directions have also been put in placefor the approval of new QPs being added under anexisting manufacturing authorization.

When a new QP is proposed, the annex revision states, theaddition must be supported by another QP at the site, whois charged with verifying that the individual has satis edthe training and other requirements necessary to perform asa QP under the manufacturing authorization.

QP Delegation Rules Clarified

The Annex 16 revision describes the operationalresponsibilities of the QP and divides them into twosections: ● those duties that must be performed personally,and ● those that can be delegated.

Duties which must be performed personally by the QPinclude ensuring that the certi cation is authorized underthe marketing authorization, ensuring that the nationallegal requirements are met, and recording of the certi cationitself.

Listed in the revision are about two dozen otherduties that the QP may delegate to other individualsas long as the QP has “on-going assurance that thisreliance is well founded,” according to the revisedannex draft.

One responsibility that may be delegated is the complianceof the active substance used to manufacture the dosageform with the importation and distribution requirementscontained in the GMPs, FMD and Good DistributionPractices (GDPs). Ensuring compliance of active substanceswith GDPs is a new expectation, which Sexton characterizedas a “hot topic” (see the story on p. 15).

Other duties that may be delegated include: ● the riskassessment for excipients and verifying the meeting ofappropriate GMP standards where relevant ● ensuringcompliance with TSE requirements and with post-marketingcommitments ● responsibility for ongoing stability studiesthat continue to support certi cation, and ● veri cationof the presence of safety features when that becomes arequirement.

DOWNLOAD FROM THE STORY:

• Annex 16 July 2013 revision

IMB’s PAUL SEXTON ON THE EU ANNEX 16 REVISIONAt the PDA/IMB conference in Dublin, Ireland in early July, IMB GMP Manager Paul Sexton dis-cussed the revised draft of EU GMP Annex 16, released just five days before for public consultation.In his presentation, Sexton highlighted the: ● reasons for revision of the annex ● changes from theprevious revision ● impact of the Falsified Medicines Directive on the responsibilities of the QP ● QPdeclaration for active substances ● revision of Chapter 5, that was out for public consultation untilthe end of June, and ● QP declaration for investigational medicinal product manufacturers.

The revised Annex 16 was released on Friday afternoon [July 5], so I have something very new to talk to you aboutand highlight in this presentation….

The revision of Annex 16 has been going on for some time. There was a consultation paper that was published towardthe end of October 2011. It basically outlined the reasons for the revisions to Annex 16. That consultation finished inJanuary 2012. It took from January 2012 until the last Inspectors Working Group meeting in June to get agreementon the draft annex, which is now out there for public consultation.

After the Inspectors Working Group provided their agreement, it went to the European Commission, and the commissionthen published it last Friday afternoon. The consultation is from July 5 until November 5. Usually the consultationperiods are three months, but this one is a little bit longer considering the summer holidays….

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INSIDE THE GLOBAL REGULATORY DIALOGUE™

If you have comments, please submit them. They are taken into consideration. Comments are also taken intoconsideration on consultation papers.

Reasons for Revision

The reasons for revision of Annex 16 [include] the globalization of the pharmaceutical supply chain, which you hearabout at every conference. I suppose this is putting more distance between QPs and the manufacturing operationsfor which they are ultimately responsible.

There is also the introduction of new quality control strategies, including a new guidance on real-time release. [Annex16] has to take into account the provision for real-time release testing.

The implications of the Falsified Medicines Directive are something that has been discussed already.

Since the original publication of Annex 16, we had the introduction of ICH Q8, Q9 & Q10, and there could be someimplications in those for Annex 16.

We also have a new interpretation document that has to be taken into account. I do not think that this [Manufacturingand Importation Authorization] MIA interpretation document has been published yet, but it has been agreed to by theInspectors Working Group. It is with the European Commission. It will actually go into the compilation of communityprocedures.

Lastly – and this was stated in the concept paper – there have been differences in the application of Annex 16 by themember states. One of the aims of this revision is to try to harmonize the thinking by member states on the applicationof the principles in Annex 16.

Key Changes

Distinction Between Certification and Release

I do not think the distinction between certification and batch release is new, but it is something that we as regulatorsare being more careful about in choosing our words. I certainly have used the term ‘batch release’ when I meant‘batch certification.’ I suppose we are getting a bit more pedantic in Annex 16 on the two processes.

The certification by the QP should take place at the site that is named in the marketing authorization and is responsiblefor this activity. Ironically, that site is referred to in a marketing authorization as the ‘site of batch release,’ which isa bit of a conflict in terminology. But it is a separate document – ‘notice to applicants’ – and this harmonization ofterminology is something that we do have to address in the future. What you might understand as being the site ofbatch release, we would understand from the marketing authorization as being the site of certification.

Also specified in Annex 16 is that the QP is responsible for assuring that the manufacturer’s authorization doesauthorize batch certification as a manufacturing activity. The MIA interpretation document will be available soon. Youwill see in that document an explanation of each of the activities within a European pharma firm. It separately identifiesbatch certification, so that every time any site is authorized for a batch certification it should be clearly identifiable fromthe manufacturing authorization.

There is going to be a period of transition between the form that you may have that has been issued to you over thepast few years and a revised form that will be coming down the pike.

One of the things that we wanted to get clear on is the distinction between certification and release. I looked back tosee if release was mentioned anywhere else in the GMP Guide. It is mentioned in the ‘principle’ section of Chapter 6on quality control.

It says: ‘Quality control is concerned with sampling, specifications and testing as well as the organization, documentationand release procedures which ensure that the necessary and relevant tests are carried out, and that materials are notreleased for use, nor products released for sale or supply, until their quality has been judged satisfactory.’ I suppose

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there is a more extensive release process, and rather than just have an administrative release at the very end, thereis something that has a broader meaning.

For that reason, in the revision of Annex 16 there is a definition of ‘release process’ and a section on the process. Itis the checking of manufacture and testing in accordance with defined release procedures, the certification step by theQP, and the assigning of the release status to the batch.

The word ‘confirmation’ was in the original Annex 16. As an inspector, I have never really used that terminologyvery much, particularly in relation to ‘partial’ manufacturing activities. This is not new, but hopefully what it means isdescribed more clearly now in the revised annex.

QPs Sharing Responsibilities

A QP at a site that is carrying out partial manufacture must confirm compliance of a batch in relation to activities thatare carried out. Every manufacturing site must have a QP – this is a requirement for a manufacturing authorization.Any manufacturing site that is carrying out a part of the manufacturing process must have a QP confirm that thoseactivities are in compliance with GMPs and other requirements.

The QP that performs the final sign-off on the batch at the site named in the marketing authorization may shareresponsibility with QPs confirming earlier steps. Again, this is something that you may not consider to be very new.But I think what it means is a lot more clearly described in this revision of Annex 16. QPs rely on other people all thetime. But a QP being able to share responsibility with another QP is something that makes it different than just sayingyou rely on somebody.

Within Annex 16 we now have a template for confirmation at the end of the annex. The confirmation performed bythe QP at the site of partial manufacture will include confirmation of compliance with GMP and with terms of a writtenagreement – a technical agreement between the sites where the QP certifying the batch takes place and the sitewhere the partial manufacture takes place.

In confirming compliance with the marketing authorization, if the QP is doing a confirmation of a partial manufacturingstep, then...we would expect that they have the details of the marketing authorization available at the site.

Another thing that is described in the annex is the possibility for QPs within a manufacturing site which has anumber of QPs sharing responsibilities of the QPs at the site in relationship to specific activities. The same principleswould apply if it was shared with a partial manufacturer that is at a different site.

A QP might be signing off, for example, on the manufacture of bulk tablets, saying ‘I am confirming compliance up tothis stage.’ Another QP could be doing the packaging step. Another QP could be doing the final certification. It ispossible for all that to be within one site.

If there is division of responsibilities, then this needs to be defined in a technical agreement, if it is between QPs locatedat different manufacturing authorization holders – so they are operating under different manufacturing authorizationholders as MIA agents. If it is QPs that are operating at the same site, it can be defined in an SOP at that site.

With the globalization as mentioned at the outset…and the increasing distance between the QP and the manufacturingactivity, or the potential for that, it is expected that QPs have detailed knowledge of the steps for which they areresponsible. That would include – and this is elaborated in the annex – detailed knowledge of the product type andthe processes surrounding the product at the stage for which the QP is responsible, and the technical advances andchanges to GMP in that particular area.

Confirmation Template

I mentioned that there is a confirmation template in the annex. This is not the full text from it. It is most of the textfrom it – I could not fit the full text on one slide. Basically the proposal is that the confirmation would include detailsof the batch, the manufacturing stage, and a confirmation statement: ‘I hereby confirm that the manufacturing stagesreferred to the Technical Quality Agreement have been carried out in full compliance with the GMP requirements of

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the EU and the terms described in the Agreement for ensuring compliance with the requirements of the MarketingAuthorization[s] of the destination country/countries….’

I noticed this and mentioned it yesterday – it is the requirements with the marketing authorization of the destinationcounty. There is a new emphasis on the legal requirements that may be in place in the destination country.

I did notice one thing that might give you your first comment when you submit them: There is an error here, in that itsays, ‘manufacturer certifying and releasing the batch.’ However, these could be different. So you have a head startif you are looking for a comment. I may put that one in as well.

Lastly [on the confirmation template] is the name and signature of the QP.

So what is the QP who is certifying responsible for? They must ensure that all of the necessary steps have beencompleted in compliance with GMP, the marketing authorization, and the legal requirements in the country wherecertification occurs or the country of destination.

QP Delegation of Responsibilities

Operational responsibilities of the QP are also described. The duties of the QP are described in the current Annex 16,but these are now divided into two subsections.

Duties which must be performed personally by the QP include ensuring that the certification is authorized under theMIA, ensuring that the national legal requirements are met, and recording of the certification itself.

But then in certifying compliance with GMP, there are going to be several aspects on which the QP is going to rely onother people and will have allocated duties for other people to carry out to ensure overall compliance with GMP. Iam only highlighting a few here – there are more listed in the annex.

One particular hot topic, of course, is the compliance of the active substance, and that it does comply with theimportation and distribution requirements for GMP, FMD and GDP – this is a new aspect, to ensure compliance withGDP for active substances.

There must be somebody assigned to carry out the risk assessment for excipients and verification of appropriatestandard of GMP where that is relevant.

Some other duties that can be delegated include ensuring compliance with TSE requirements and with post marketingcommitments. From a validation perspective, maybe this could be something where the assessor has said, ‘you haveidentified that you are going to perform continued process verification.’ So this could be something that the QP couldensure is carried out but can be delegated to someone else.

Other activities that can be delegated include responsibility for ongoing stability studies that continue to supportcertification, and any investigation that is ongoing, which must be completed to a level that supports certification – soany corrective actions would need to be completed.

Any ongoing complaints, investigations, or recalls do not negate conditions for certification. If you are getting issueswith complaints, say, for a particular aspect of a product, is it appropriate to continue to release products into themarketplace which may potentially have the same issue?

Lastly, the presence of safety features, when that does become a requirement, must be verified for human medicineswhen they fall into the relevant category.

Parallel Importation Responsibilities

There is also guidance on parallel importation and parallel distribution. This is a new aspect covered under Annex 16.The product has to be sourced from the authorized supply chain and must have been certified by a QP at the originalmanufacturing site. The QP then, at the parallel importer, for example, certifies that the repackaging operation has

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been carried out in compliance with the parallel product authorization and that re-packaging has been performed incompliance with GMP.

Another requirement is that the safety features on the original pack be verified prior to the repackaging operation.

Importation was considered to be an area where there was some discrepancy between member states in how theyapproached this subject. There are importation requirements already stated in Annex 16, but it is restated moreclearly in the new Annex 16.

The importation activities themselves consist of receiving, sampling, storage of quarantined batches, batch certificationand the release.

Imported Batches

Physical importation is new terminology, which is introduced under the MIA Interpretation document. This means asite which is basically acting as the site for the batches physically received, but it may not be the site which is carryingout the certification step.

The certifying QP can share responsibilities in relation to any activities carried out at a site in the EEA and confirmedat those EEA sites by another QP. And I suppose the last point is the one that was considered to have the mostdiscrepancy between the EU member states – that imported batches should be sampled after arrival in the EEA.

With regard to the testing of imported batches, that requirement is defined in the directives. There is a provisionnow for real-time release testing at a third country site. So if the site has been approved, and is in the marketingauthorization, an inspection would have taken place at that third country site in relation to real-time release, so thereis no need to carry out a re-test of the particular quality attribute in the EU.

There is also some guidance on the scenario where you may have different finished product batches originating fromthe same bulk. I think this was also in the original Annex 16. It does provide for leveraging the full testing on anotherpart of the batch, but it says that assay and ID should be performed as a minimum on any other part of the bulk that isused for finished product lots. If you are going to leverage the test data from one section of the batch, obviously thestorage and transportation conditions must be verified as equivalent.

GMP Assessments by Third Parties

There is a section on reliance on GMP assessments by third parties. There has already been a Q&A on EMA’swebsite about this in relation to active substances, and I do not think you will find this is very different in terms ofexpectations. But the QP does have a role in ensuring that there is an assessment carried out and concurring withthe outcome of any third party audit.

The QP should be aware of audit outcomes and whether there is a critical impact on product that needs to be takeninto account before certifying any batches.

Deviations from GMP and MA

One of the aims that was expressed in the concept paper was to include the provisions that are included in the “ReflectionPaper” published on EMA’s website. In this section, it deals with unplanned and unexpected deviations in terms ofthe marketing authorization, but also from GMP. I believe this was a request that came in as a comment on the conceptpaper that asked, ‘why is it in terms only of deviations from the marketing authorization?’ So there is a provision in thisfor dealing with deviations from GMP, which are the vast majority of deviations that would be encountered.

The proviso is that the registered test specifications must be satisfied for the API, excipients and finished product.There should be an assessment carried out under quality risk management principles that concludes that there is noadverse impact on quality, safety or efficacy.

There should be consideration for inclusion of the batch in the on-going stability program, and the QRM in the case

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of biological products should take into account that a small change may give rise to an unexpected and more significantimpact.

The QP certifying must be aware of and consider any deviations with potential impact for compliance with GMP or theMA. And lastly, the QP must ensure that the legal requirements in the destination countries are satisfied.

Batch Release

The batch release step is more of an administrative step assigning the release status that takes place after QPcertification in some cases, but it also may be an integral part of the QP certification, particularly if there are electronicsystems used.

Certification and release may be one in the same step. It is possible for this to take place at another authorized site.Particularly where this is the case, there should be safeguards in place to prevent any accidental release of productprior to certification.

The means by which the QP certifying notifies the site where release takes place should be formal and documented.This can be electronic, of course, in accordance with Chapter 4.

Impact of the FMD

I want to mention briefly the impact of the Falsified Medicines Directive. It does not apply to IMPs. It does not applyto veterinary products.

Some new requirements – general requirements that are coming in under the FMD – include mandatory audits ofmanufacturers, which might have been an expectation in any case. However, auditing of distributors of activesubstances is something that is new, I believe, for manufacturers. This will also be a new area for inspectors.

Risk assessment of the excipients…and the checking of safety features where appropriate were mentioned earlier.

For manufacturers of finished products in Ireland who are importing an active substance, we expect them to registerwith IMB as an importer of active substances. There may be some slight differences in that approach across theEU.

[Regarding] IMB expectations for sites importing active substances, we expect that the manufacturers have accountedfor the importation requirements within their quality system, and that they should ensure that the relevant recordsassociated with use of active substances are satisfied.

We are expecting one of these three criteria to be available at the site: ● evidence that importation is from a countrydeemed to be equivalent ● a written confirmation to support use of active substance, or ● a waiver from the requirementto have written confirmation. Here in Ireland, we are issuing a formal waiver document to manufacturers who haveapplied for it where it is considered appropriate to waive in the first place.

QP Declarations

The QP declaration for API is ten pages and was published a couple of years ago. It is a Quality Working Partydocument, although it was also reviewed by the Inspectors Working Group. The finalized document is still in gestation.I think there were quite a number of comments on the document, but it does go into quite a lot of detail regarding whatis expected in terms of elaboration of the actors in the supply chain. And it will also focus on the basis for declaring thecompliance of the actors and whether it was based on personal knowledge, or done by a third party, and so on.

For completeness I will mention here that Chapter 5 also reinforces the concepts in the QP Declaration. It now requiresthat the manufacturer has detailed, documented evidence of the full supply chain – all actors in the supply chain foran active substance. It also mentions about the requirements for audits of API manufacturers and distributors andlikewise in relation to excipients that are considered to pose risk.

This document is more recently published: It is a template for compliance of a manufacturer of an IMP in a third

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country. The purpose of this document is to harmonize submissions for clinical trial applications in a third country.

In this document, the QP must provide the basis for the declaration of compliance: Was it based on personalknowledge? Was it carried out in the last three years? Was there an audit by a third party in the last three years?And if there are any other means, then it must be justified.

If we are processing a variation to add a third country manufacturer for an IMP to an Irish manufacturer’s authorization,we actually ask the QP for a declaration in relation to that third country manufacturer. We welcome this formalized typeof template. It is certainly acceptable here for the purpose of variation to a manufacturer’s authorization. Consultationon the template finished in April of this year.

Conclusion

QPs have other roles not described in Annex 16. But they do tend to be a person that the regulator goes to, becausethey really are a person that is deemed to have knowledge of the manufacturing process, and they are a responsibleindividual that has defined responsibilities for manufacturing activities.

They are often a key contact person in relation to investigations of complaints, quality defects or recalls…. Themarketing authorization holder is certainly the first point of contact in a recall situation. But in terms of trying to get thedetails of investigations, the QP will often be the key contact.

I also mentioned that the QP may be asked to provide statements to support variations to a manufacturer’s orimporter’s authorization. We also have a requirement that if there is an additional QP being added to a manufacturer’sauthorization that their addition is supported by another QP at that site to verify that they have satisfied the trainingrequirements and so on that would be mandatory for adding someone as a QP to a manufacturing authorization.

With all these increasing expectations, how can the QP cope? There are defined responsibilities for manufacturershere in Ireland. It is part of the conditions of a manufacturer’s authorization that they must equip the QP or providethe systems necessary to allow the QP to carry out his or her duties.

Marketing authorization holders also have a key role to play. Sometimes, I think, they may just focus on the businessaspect. But they have key roles to play. And that is why the inspection of marketing authorization holders is somethingthat has been introduced to enforce the greater regulatory focus and responsibility that is at those sites.

Underpinning all of this, or course, there should be a pharmaceutical quality system. If these activities are atdifferent sites, then technical agreements are expected to fill that gap and bridge the quality systems, if there aredifferent quality systems that are operating.

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Process Validation Regulatory Submissions Quality Assurance

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INTERNATIONALBurden of Pre-Inspection Submission Requests from Agencies Outside the USand Europe is Growing

Pharma industry experts are expressing concern with a newtrend of emerging country agencies requesting signi cantamounts of manufacturing and facility information priorto performing GMP inspections and are proposing thatthe international community work toward a more clearly-de ned, manageable, and harmonized approach.

Primary concerns include the burden of preparing theinformation when what is requested has no clear boundariesor level of detail speci ed and does not correspond toalready-prepared internal information. Equally concerningis the potential for misinterpretation of complex informationthat is normally provided during an inspection whencompany experts are on hand to provide clari cations oranswer questions that may come up.

When the documents are provided in advance, a considerableamount of time and effort is required to prepare them, andin many cases to translate them, and to ensure that they areclear and in the proper context. In turn, time must thenbe spent communicating with the requesting agency toanswer questions and provide follow-up information andexplanations. Firms are nding that the pre-inspectionrequests can be more burdensome than the inspectionsthemselves and are diverting valuable quality resourcesfrom more productive activities.

At a conference on the “Current and Emerging EURegulations and Inspection Trends” co-sponsoredby PDA and the Irish Medicines Board (IMB) inDublin in July, Boehringer Ingelheim (BI) AssociateGMP Auditing Director Harald Scheideckerhighlighted the problems that these advancedocument requests are creating for facilities suchas his that supply internationally and suggestedalternative approaches that could help avoid them.

Scheidecker’s analysis at the July conference of his rm’sexperience with pre-inspection submissions complementeda related analysis that he provided on the growing burdenof redundant inspections by various agencies at a 2012workshop cosponsored by PIC/S and PDA (see IPQ“Monthly Update” April 2013, pp. 28-37).

At both meetings, the BI quality of cial advocated the needfor more international coordination and communication andfor forums such as PIC/S and ICH to help nd a harmonizedpathway forward.

GMP information review outside of inspectionsis also getting close attention at FDA as part of itslook into the value of better defi ned quality metrics(see IPQ “Monthly Update” June 2013, pp. 12-20).

FDA sees the potential for a set of objective, transparentmetrics – agreed to by industry and made available to theagency – to provide a platform for transitioning from aninspection to a more proactive surveillance mode that wouldsigni cantly extend its oversight reach.

The agency anticipates that the use of these industry-widemetrics would enable it to better target which sites, andwhich products, processes and systems at those sites, requireagency attention, and decrease the inspection burden onsites that have robust quality systems.

FDA’s exploration in this arena could result in a modelaround which the international regulatory communitycould, in turn, coalesce. Unlike the current trend towardpre-submission of the same kind of extensive process,procedure, and batch documentation that has been availableon inspection, the metrics approach would be potentiallyboth easier for industry to handle and provide more valuein regulatory decision making.

Korea and Turkey Provide Case Studies

Scheidecker discussed advance document requests BI hasreceived from the Korean FDA (KFDA) and the TurkishMinistry of Health (MoH) as examples of the recent trend ofauthorities outside the US making numerous, detailed, andoften poorly-de ned pre-inspection document requests.

“We have a launch site in Ingelheim, and we launch severalproducts a year,” he explained. “So it was not only once,but for each new product we launched. They asked forextended content, much more than a site master le.”

KFDA released a guidance in May 2012 detailing theincreased information it now requests to review prior to anon-site inspection related to NDAs, API applications, drugproduct manufacturing sites and drug product packagingsites.

“This is a huge package of documents,” Scheideckerstressed. In addition, the data must be presented “in a waythat somebody else can read it and understand it well.”

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Also of concern is that the documents requested containspecialized content that is not routinely prepared by most rms in a single document. For example, drawings wererequested that contain the position of equipment, gauges,control pressure differentials, and position of pest controldevices. Preparing one document that contains all therequested information and presents it clearly the BI of cialcharacterized as “not easy.”

The Turkish MoH authored an internal guidancein 2009 in which it requests certain documents as apre-requisite for performing an onsite audit.

“I can tell you that we have gone back and forth many timeswith the Turkish ministry to clarify that the documents aresuf ciently prepared and presented,” Scheidecker noted.

Of particular concern in the case of Turkey is that theinformation requested is generally provided to otheragencies during inspections when experts and members ofthe escort team can “immediately act if we see that there issome confusion coming up or if there is some misleadinginterpretation in the information that we provide. This doesnot happen if we have to supply it on paper up front to theinspectorates.”

Harmonize Around Existing Documents

Harmonizing agency expectations for pre-inspectionrequests around already-approved and vetted documentsthat undergo increased internal scrutiny and annual reviewswould greatly decrease the burden now placed on the rmsbeing inspected and provide better information to the

inspectorates than ad hoc reports, Scheidecker stressed.

For example, site master fi les (SMFs) as defi ned byPIC/S, along with the CMC sections of US and EUmarketing applications could be made availablein advance of inspections and provide adequateinformation to the inspectorates outside the US andEurope.

He maintained that communication between the authoritiesseeking the advance information and the authorities thathave the SMF and registration documents on le “wouldhelp to save effort and time” and allow the manufacturing rm to focus more time and energy on “the quality of ourproducts and the safety of our patients.”

BI has suggested that the Turkish and South Korean agenciesand others contact European authorities to obtain the SMFand registration documents and answer questions in lieuof requesting them from the rm. “But there is nobodywho is really doing that,” Scheidecker explained. “There isfrom an industry point of view a hope that there is morecommunication between authorities on these topics.”

The BI offi cial suggested that industry could workwith the inspectorates to harmonize the contentof SMFs and drug master fi les (DMFs) so thatthey would work to satisfy the pre-inspectionneeds. The standardization and syncing of annualproduct reviews could be another focus of thisharmonization effort.

“Maybe these kinds of standardized documents will

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also meet future expectations of these authorities that aredeveloping their GMPs,” Scheidecker commented.

The information inspectorates are requesting “should beprovided in a way that is not misleading and also readableand understandable far away from the local site,” hemaintained. “There is a wish that maybe all the inspectoratescome into contact to see how they can harmonize. The ICHand the PIC/S initiatives can help much in this regard.”

Q&A Explores Additional Details

In the Q&A following his presentation, Scheidecker wasqueried regarding: ● whether the advance document requestsreduced inspection frequency and time by the requestingagencies ● the need to supply copies of original documents● the company paying expenses for an inspector from anemerging cash-strapped agency to perform a plant visit, and● the potential role of PIC/S in standardizing checklists orother documents that may satisfy agency requests.

Scheidecker cited the example of KFDA inresponding to the question whether fulfi llingthe document requests resulted in more focusedinspections or delayed inspections by the requestingagencies.

If suf cient documents are provided, he explained, KFDAaccepts them in lieu of an inspection, and will only performan inspection if the rm les a new formulation. If asecond product is led using the same already-inspectedformulation, “then this would be covered by a more intensivereview and providing of information documents.”

For some African countries, BI has offered an FDAestablishment inspection report (EIR), and the agencieshave responded by prolonging the duration of the rm’sGMP certi cates.

Scheidecker commented that, in his experience, providing theinformation up front had no “direct effect on the inspection”when an inspection was subsequently performed. “We haveto show the same documents during onsite inspection. Theycome with the same questions again, and if we reference andsay ‘okay, you already have that information up front,’ weget no change to the time we have to spend to go throughthe systems again.”

Another attendee explained that her fi rm was inthe process of providing a plant master fi le for theTaiwanese authorities and asked the BI offi cial ifshe needed to send copies of the original documentsas part of the document request.

Scheidecker responded in the af rmative. “They ask forthree executed batches and for all raw data corresponding

with the CoA. This was more dif cult than an onsiteinspection – more data and more workload. For the systemapproach, what we see is that we have a lot of informationin the site master les, but that was not enough. They ask formore and more.”

He reiterated his suggestion to update or review the contentof the site master le “to make it more useful in regards tothe latest information which is requested by these emergentcountries.” In addition to creating a common standard,another bene t would be to have the documents put on aperiodic review cycle in-house.

“What we do at the moment is a case-by-case preparationof the documents, and so we have no review cycle. But wecan also put it on le or archive it.” Currently, he explained,“there is a not a systematic approach for providing thisinformation.”

Amgen Head of External Affairs for Europe,Stephan Ronninger, who presented on globalharmonization and inspection practices and trendsat the session, commented on the need to translatedocuments and the resulting challenges.

“Especially with Turkey,” he noted, “you have to translatesome of the documents, even extensive documents, into theTurkish language on short notice. So your colleagues at yourTurkish af liate cannot double check to see if the translationwas right or not. This can provide for confusion.”

PDA Europe President Georg Roessling commented thatin 2014 PDA is hosting a meeting in Turkey, and hopesto continue some of these discussions with the Turkishauthorities at that time. He also noted that Turkey has nowapplied for membership in PIC/S.

Adrian Johnson, who works in Amgen’s facility inthe Netherlands, pointed to a translation experiencehe had with the Japanese agency when working ata previous employer.

“The rst request for documentation was a list similar to theKFDA list that you indicated. But before all the documentswere prepared, they requested more documents. Theyrequested translation beforehand, and then they gavethemselves a three-week review period because theinspectors could not afford to come to our facility.” Hesuggested that it might be useful to pay for the inspectors’travel rather than having to prepare and submit all the paperdocumentation.

Scheidecker commented that he had suggested thatapproach at BI. “That is quite less work than having twopeople working two weeks preparing all the documentsand getting all the back and forth of information.” So far, heexplained, the idea had not gotten traction at his company.

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Industry consultant and session moderator KarenGinsbury addressed the possibility of having PIC/Splay a role in standardizing the content and formatof pre-inspection document requests.

“The question,” she commented, is “whether we, thinking ofcost-effectiveness, can work to at least standardize it withinthe framework of the PIC/S countries. Just like PIC/S has atemplate for a site master le, maybe they could think aboutstandardizing a checklist of documents that, on a routinebasis, most major inspectorates would or might like to seebefore the inspection. And then that might be a basis for

going to some of those who are outside of PIC/S and lookingat what is going on within PIC/S that might help.” She alsoacknowledged that sometimes a case-by-case approach isnecessary.

IMB Head of Inspections John Lynch commented that“PIC/S may well have a role here, given that these countriesare applicants for membership. We can look at the systemsin PIC/S and whether we need to develop somethingspeci c.” He said that he “will pass these comments” tohis IMB colleague Anne Hayes, who is a member of theexecutive bureau of PIC/S.

BI’s HARALD SCHEIDECKER ON THE PROBLEM OF PRE-INSPECTION SUBMISSIONS

At the PDA/IMB conference in Dublin in July, Boehringer Ingelheim Associate Director of GMP Au-diting Harald Scheidecker discussed the recent trend of inspectorates outside the US and Europerequesting more documentation to be submitted prior to their inspections and the impact of facili-ties such as those of BI that supply internationally. He addressed: ● the industry position ● casestudies involving KFDA and the Turkish Ministry of Health ● areas of harmonization and conflict ●the new approaches and the associated risks, and ● possible solutions.

I am being optimistic that people will take these thoughts home and that industry representatives will share what Ipresent to you with your own companies. Maybe at a later point in time, in one of the future conferences, you canexchange your experience in that regard.

For the IMB, and for the authority representatives, I would like to ask you to take the information with you and maybetake the opportunity to ask your inspectorates to also maybe address the problems I will present to you.

What I would like to talk about is the trend I see in the last years of new authority approaches mainly coming from the

so-called emerging markets. They have special interpretations. Also we have heard from Stefan [Ronninger] that theirGMPs are still under development, so they have new tasks and new ideas on how to prepare and plan for the audits.

I will give you some examples of the changing tasks that I have seen – for example, assigning products into drugproduct formulations in some kind of grouping. Some of the authorities like to group. They are also changing theinspection focus from a product-related view to risk management and system robustness. This is not really new for us,but it gives us new tasks in preparation of these inspections.

We also have to address that some of the health authorities disregard the EU GMP certificates, which is also a problemthat can cause problems in the future. Nevertheless, the big issue is that we have requests for extended documentaudits prior to onsite audits as a new approach.

Industry Position

Let me give an industry position. It is very clear that we would we like to confirm our authorities’ expectations bydemonstrating our compliance for the products and the market approvals. That is for sure. There is no doubt about this.But on the other hand, we expect harmonized standards. This whole conference has been going around this topicof harmonization. We would like to provide already implemented and routinely used documents instead of preparingcertain information by single documents or declarations.

Now we come to possible targets that I see we can have. This is my question for you: Could we harmonize theinformation which is requested?

Maybe there are developments there. There are new questions coming out. There are new ways we have tocommunicate. But nevertheless, is there still room to harmonize that? Could we use our existing tools to answer pre-

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audit requests? This would be our hope….

I have prepared two examples that I would like to present to make more clear what I have detected in the past year.

KFDA Information Requests

One case involves KFDA, the South Korean FDA. The agency released in May last year a guidance on management ofpre-evaluation of GMP for pharmaceutical products. The inspectorate requires more information and more documentsto review prior to an inspection on site for NDAs, API applications, drug product manufacturing sites, and for drugproduct packaging sites.

KFDA requires more GMP documents. They ask us to provide [the information] numerous times. We have a launchsite in Ingelheim and we launch several products a year. So not only once, but for each new product we launched,they asked for extended content, much more than a site master file. They asked for the NDA and also the electronicbatch record, and the electronic master batch record for three executed batches.

This is a huge package of documents. Of course, the GMPs force us to have them in a readable form. But what ismeant by readable form? It is the kind of readable document that needs explanations. And to send that up front to aninspectorate could be very difficult.

Also the certificate of analysis [CoA] was requested with the corresponding raw data for three batches. What comesup is: What is the corresponding raw data to the certificates of analysis? Where does it start? Where does it stop?What is included? What is excluded?

An extended validation document package was also asked [for] including validation of corresponding utilities. You canimagine that this quite simple question can bring up a big workload. What is included? What is excluded? What kindof work document [do] I have to present and have to send upfront to prepare for an onsite inspection?

One of the areas of conflict I see is that the requested content and the layout of the drawings are not routinely

prepared. Drawings were requested that contain position of equipment, gauges, control pressure differentials, andposition of pest control devices. Making sure that your company has a single drawing which answers all of thesequestions correctly, and maybe making a different kind of technical drawing is not easy, because usually during aninspection you can explain them and take the experts together with the drawings, and follow the single drawing or acouple of drawings [in the plant] to make this very clear for an external review.

They also asked for lists with a huge amount of detail – [for example], lists of SOPs. This is the most crazy requirementor request I ever have had in my career as an auditor. … At the site in Inglheim we have 3000 employees, maybe wehave 2000 SOPs. What is in and what is out of scope? Mainly we have SOPs related to the products.

They also requested lists of automated systems as well as computers and other related systems. Let us think aboutwhat that could mean. Is it all SIP modules, all excel sheets? If you look for computerized systems, we have a list ofthose in-house. But to provide it up front in preparing for an onsite audit is not an easy task to fulfill.

A huge number of attachments are requested. An example is electronic batch records – I addressed that earlier.Also requested is information on the water systems, trend analysis, CoAs for each point of use, and all OOSs includingactions taken. Another example is room classification and environmental data for the whole last year including whichrooms are covered by this approach and how many buildings you have. You have to present this data in a kind ofpackage where you will summarize it and present it in a way that somebody else can read it and understand it well.

Turkish Ministry of Health Document Requests

The second case I will present to you is from the Turkish Ministry of Health. They authored an internal guidance in2009 in which they request a couple of documents as a prerequisite for performing an onsite audit. I can tell youthat we have gone back and forth many times with the Turkish ministry to clarify that the documents are sufficiently

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prepared and presented.

As an example, they request a list of key personnel and training records. It is quite easy for all of us to present thetraining and education of a qualified person. But what about the production head? Or the CEO? These are also keypersons in our modern management systems. It is actually really challenging for me to show what kind of training andeducation the CEO has performed in the last year.

Facility diagrams were also requested, and all cleaning procedures. Does it mean all? Where to start? Where to stop?Also a list of OOSs, deviations, and manufacturing procedures governing the material sampling release and storage[were requested]. How can you do this packaged in the correct way for the ministry? They also asked for the serviceproviders for the pest control, sampling routes, sampling SOPs. The question is where to start and where to stop, andwhat kind of information is really requested to make it convenient for the authority.

Inspection certificates and inspection reports, product details like process instructions, mixing sequence, mixing time,and temperatures all need to be provided upfront.

This information is typically covered in an onsite inspection. I have no problem with all of these questions. We showthe information routinely in onsite inspections to the inspectors, but not in a way that the inspectors will read themalone. We have experts on site who can explain the combination of different documents and explain the drawingsand give sufficient information. And, I think more importantly, we can, as an escort team, together with the expert,immediately act if we see that there is some confusion coming up, if there is some misleading interpretation in theinformation that we provide. This does not happen if we have to supply it on paper up front to the inspectorates.

Areas of Harmonization and Conflict

If we look for areas of harmonization…I think that the site master file is a good source of information. This shouldbe sufficient for preparing and planning for inspections. I am referring to the site master file according to PIC/S. Thevalidation master plans should be accepted in accordance with Eudralex Annex 13 for drug products and Annex 15 fordrug substance. These are standards that should be sufficient….

For the manufacturing scheme I would say that what is already filed with the authorities is sufficient and enough toreference. [For example, in the common technical document, the filed information on: the manufacturing scheme(P3.3); analytical methods (P5.2); and drug substance (S4.1).]

The areas of conflict are: ● excessive information ● the level of detail and purpose is not always clear for us as anindustry to answer correctly, and ● missing communication between local and foreign authorities.

So we often ask, ‘please, can you – the Turkish ministry, the South Korean ministry, or the Kenya ministry – come intocontact with our local authorities?’ We know that our inspectorate also is happy to answer the questions. But there isnobody who is really doing that, who tries to communicate between the authorities. There is from an industry point ofview a hope that there is more communication between authorities on these topics.

Here are more examples: For the Turkish ministry, they requested a readable site plan including specific informationprinted on A3 paper. So we suggested sending the electronic data that they can print in their office, and the responsewas, ‘please provide it on paper in A3 in readable form.’ To me the question is why it is not sufficient to just providethe site master file.

They also request a list of SOPs. Why? We address most of the important system SOPs and relevant SOPs that drivethe quality system…in summary form in the site master file. So why is that not sufficient?

New from the Turkish Ministry of Health: They specifically ask for a list of storage conditions of imported products. Ifthe products are subject to cold chain, [also requested are] validation reports of countries that have similar conditions,and detailed information of transport vehicles, equipment and procurement contracts. So this is new as a confirmationof GDP. It is also an indicator of how the preparation and planning of the authority inspections is driven by and will be

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INSIDE THE GLOBAL REGULATORY DIALOGUE™

developed by new subjects.

The sharing of inspection reports by other authorities is not possible in Germany. This also is the reason why werequest and would like to have more communication between the authorities.

New Approaches and the Associated Risks

I would like to highlight the new approaches and the associated risks:

● The requested information is typically prepared and shown by industry in onsite inspections. I think there is aconflict.

● The expected details and drawings and all lists are often not depicted on one scheme. We have several of thesetechnical drawings. We have the pressure differentials. We have the personnel work flow and the material flow.We have all these different schemes. And this, I think, can only be understood if somebody from the companyis present and can give the links between the information, or you have the minimal idea about the systems thatwork onsite.

● In the end, it is not easy to prepare this information adequately. In our experience it often results in misinterpretationand misunderstanding. So it takes a lot of time and communication with the inspectorates to prepare them for theonsite inspection at our site.

Therefore, the conclusion is that maybe this practice we observe is not beneficial, because onsite inspections, I think,cannot be transferred to a desk in a different country.

Possible Solutions

What could be possible solutions from an industry point of view?

We hope that we can have harmonized tools. Maybe we should think about review of the site master file or drugmaster file contents to meet the authority inspections of these emerging countries and their inspectorates….

Maybe we also have to sync and harmonize the annual product review. This is a very interesting document with alot of information. Maybe these kinds of standardized documents will also meet future expectations of these authoritiesthat are developing their GMPs.

Also, the acceptance details given in our registration documents should be sufficient for preparing for audits….

Nevertheless – this is also important – we will not keep any inspection team from a customer or an authority fromfurther information that maybe they need. So the list of information and documents requested will be provided. Butas my examples maybe show you, they should be provided in a way that is not misleading and also readable andunderstandable far away from the local site.

In summary, industry should acknowledge the need for inspection teams to ask for information. Yes, of course we do.However, we would like to have similar requests from inspectorates. There is a wish that maybe all the inspectoratescome into contact to see how they can harmonize. The ICH and the PIC/S initiatives can help much in this regard.

Already prepared information should be sufficient to prepare country-specific inspections by nominated inspectors.This would help to save effort and time to answer questions prior to inspections. In this regard, we can focus ourworkloads to the quality of our products and the safety of our patients.

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NSF International is working with the InternationalPharmaceutical Excipients Council (IPEC) and FDA toturn the IPEC excipient GMPs into a risk-based, certi ablestandard with global applicability by the end of 2013, asrecognition of the importance of excipient control continuesto grow.

ANSI NSF-IPEC 363 will provide a stand-alone, qualitysystem-based GMP standard that industry and regulatoryagencies can use in evaluating, auditing, and certifyingexcipient manufacturing and quality. It is intended to makeexcipient manufacturing risk more transparent and drivebetter knowledge management.

NSF is one of the few organizations accreditedby the American National Standards Institute(ANSI) to develop “national consensus standards”– standards that can be adopted and used by USgovernment agencies such as FDA when the agencyhas not developed its own standard. Participationof industry suppliers and users, FDA and academiain developing the excipient GMP standard – alongwith a public comment process – means that thestandard will be fully vetted prior to its adoption.

NSF International is a not-for-pro t global independentpublic health organization that writes standards, tests andcerti es products, and does training and auditing for thefood, water, and health sciences industries.

NSF has announced that it will be acquiring InternationalPharmaceutical Excipient Auditing (IPEA) from IPEC withthe goal of strengthening IPEA’s reach and capabilities inthird-party auditing and certi cation. The acquisition isscheduled to be completed by the end of the year.

IPEA will become part of NSF’s recently-established HealthSciences Pharma/Biotech Division, led by Neil Wilkinson.During his career at AstraZeneza, Wilkinson played asigni cant role through ICH and EFPIA in internationalquality policy development and harmonization efforts.

In 2010, NSF acquired David Begg Associates (DBA), whereWilkinson was a partner with responsibility for its growingUS presence. Established in 1986, DBA has focused ondeveloping expertise in pharmaceutical quality manage-ment, regulatory compliance, and training – in particular,training programs for quality professionals globally andcerti cation preparation for the quali ed person (QP) inEurope.

NSF’s health sciences reach further expanded in 2012 with

the acquisition of Becker and Associates, a Washington,D.C.-based consulting rm with strong medical deviceexpertise. Ron Johnson, a former FDA eld and centertopsider, is continuing to lead the Becker group for NSF.Johnson’s career at FDA included serving as director of theagency’s Paci c Region, compliance of ce director at theCenter for Devices and Radiological Health (CDRH), andchair of various FDA eld committees.

363 Matches Control Expectations With Risk

The shift in the pharmaceutical regulatory paradigmtoward the quality-by-design (QbD), risk management,and quality system principles embedded in ICH Q8-10 isbringing excipient control more squarely into the regulatoryfold. A central concern for the international pharmaceuticalcommunity is how to make this transition happen in a waythat is as manageable and ef cient as possible for suppliers,users, and regulators.

The 363 consensus standard will provide a consistentyardstick to measure the performance of excipientmanufacturers. In turn, it will provide a framework forexcipient quality control and risk management that isconsistent with the ICH Q8-10 principles.

The content and signifi cance of the new NSF-IPEC363 standard drew signifi cant attention at an April30-May 1 “ExcipientFest” conference in Baltimore,Maryland, sponsored by IPEC.

A breakout session was held on the standard at which NSFExecutive VP Lori Bestervelt provided an overview of itsdevelopment and objectives.

Citing excipient provisions in the FDA Safety and InnovationAct (FDASIA) (see IPQ “Monthly Update May 2013, pp. 16-22) and the EU Falsi ed Medicines Directive (FMD) (seeIPQ “Monthly Update” May 2011, pp. 27-35), Besterveltexplained that the 363 standard will provide a tool “to helpus navigate in the new and changing landscape of rules andregulations.”

She noted that a key component of the new standard isits incorporation of a risk assessment process that can beapplied irrespective of the particular excipient and that willkeep the standard from becoming too prescriptive.

In a plenary session at the ExcipientFest meeting,CDER Offi ce of Drug Security, Integrity and Recalls(ODSIR) Associate Director for Risk Science,Intelligence and Prioritization Steve Wolfgang – a

NSF-IPEC 363 GMP Standard Will Provide Risk-Based Approach for Auditingand Certifying Excipient Manufacturers

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member of the NSF-IPEC 363 drafting committee– provided a “regulator’s perspective” on thestandard, echoing Bestervelt on the importanceof its risk assessment approach (see box at theend of the story for Wolfgang’s remarks on the 363standard).

The use of quality risk management (QRM), he said, allowsthe tailoring of individual approaches “to prevent againstcontamination and mix-ups and to also ensure that end-user requirements are consistently met with a high levelof consideration of pharmaceutical quality and patientsafety.”

Wolfgang commented that, although the standard willnot cover “every single aspect” of excipient quality, it willprovide a “baseline” that will help a pharma companydetermine “whether or not an excipient should even bethought about being used.”

At a “Pharmaceutical Supply Chain Workshop”co-sponsored by PDA and FDA in Bethesda,MD in early June, Huber Engineered MaterialsGlobal Quality Director Dale Carter – immediatepast chair of IPEC and also a member of the 363drafting committee – emphasized that the use ofrisk assessment in the standard “has changed theparadigm” in excipient quality assessment.

“It is forcing the excipient companies to understand whythey do things and to prove it to an auditor,” he explained.“So now you defend why you are wearing a hairnet, not just‘we got one on, don’t worry about it.’ Instead of just puttingon the hairnet and walking in, they understand the purposeof the hairnet – what they are trying to control.”

If companies and individuals understand the risks andwhy controls were put in place to mitigate the risks, Carterpointed out, then when older employees retire and theyounger people take their place, “they understand how tokeep these things current because they understand the risk.They are not just trying to copy something.”

The standard requires “a lot more than a check in a box,”Carter stressed. “It is a lot of justi cation for what they aredoing, why they are doing it, and why is it acceptable.”

IPEC Excipient GMPs Provide Baseline

At the PDA workshop in June, Carter provided a history ofthe NSF-IPEC 363 standard, noting that it is based on the IPECexcipient GMPs that were introduced in 1995 and revised in2006 in collaboration with the UK’s Pharmaceutical QualityGroup (PQG).

The 2006 version “emphasizes some key points that are not

in, say, an ISO 9000 quality management system, although itutilizes the framework of ISO, with the sections set to alignwith the ISO 9001 set of quality systems.” Added in the 2006version were elements pertaining to the management of“signi cant” changes, certi cates of analysis, stability, and“some more speci cs and guidance on infrastructure, workenvironment, and personnel practices.”

The 363 standard, Carter explained, represents anevolution from a voluntary check-the-box exercise,generally performed when auditing an excipientmanufacturer against the IPEC GMPs, to a qualitysystem-based approach that will be offi ciallyrecognized as a standard, at least in the US.

Although the IPEC GMPs are “widely used” and writtenin such a way that they can be applied to a “diversity ofexcipient manufacturers,” Carter’s experience has been thatauditors using them generally focus on document controland the standard parts of a quality system, rather than onthe particular product of interest and what is importantbased on how the product is used.

He also pointed to the variability in audits based on theauditor’s particular experience and background. “A lotof them came out of a lab,” Carter noted. As such, theytend to spend more time in the laboratory rather than in themanufacturing plant “where all the risks are.”

Recognizing the need to move to a systems-basedapproach for the evaluation of excipients that moreclosely mirrors the principles in ICH Q8-10, IPEC

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approached NSF in 2009 to work with it in craftinga new standard.

Carter explained that IPEC chose NSF because of the rm’shistory of writing consensus standards under the ANSIprocess – for example, for the sanitary design of restaurantequipment – and its success in working with entities withdiverse backgrounds during the standard developmentprocess.

“Using NSF and their process, this year we will come outwith an of cial ANSI standard. We are still in the laststages of ne tuning the language and validating the nalversion.” The working title is “NSF-IPEC 363GMP – GoodManufacturing Practices for Pharmaceutical Excipients.”

IPEC formed International Pharmaceutical ExcipientsAuditing (IPEA) because “it wanted to show the world whata true good auditing group should look like – how to do itright, how to do it so that you can share your audit reportsand have con dence in that,” the IPEC past chair explained.“And that was our main goal as a service to our members.Now we want to move on to set auditing standards.”

NSF-IPEC 363 vs. EXCiPACT

At the IPEC/ExcipientFest conference, Carter addressed acomplementary effort – EXCiPACT – that launched in the USin April, and explained how it differs from NSF-IPEC 363.EXCiPACT was put together by IPEC’s US and Europeanbranches along with PQG, the European Fine ChemicalsGroup (EFCG), and the Federation of European ChemicalDistributors (FECD).

Carter explained that EXCiPACT also uses the IPEC excipientGMPs as a basis, but marries them with the ISO qualitymanagement standards and good distribution practices(GDPs) “so that you can get an EXCiPACT certi cation forGMP to go with your ISO certi cation.”

By contrast, the ANSI standard is taking the IPECGMPs and creating a stand-alone quality system-based GMP standard. “So that based on qualitysystems and the GMP practices that are built intothat, managed by the quality system, you couldhave an audit of a facility that said, ‘okay, theimplementation of GMP at this facility can becertifi ed or not.’”

“To avoid confusion,” Carter said, “there are not twodifferent certi cation standards. There are two differentapproaches to certify to the same GMP. One is utilizingthe ISO part, which is very popular in Europe and whythe Europe group went through that. And the other is as astand-alone standard, which is more in the US model.”

In addition, the ANSI process being used for NSF-IPEC363 includes “a lot more rigor and documentation.” Henoted that “great care” was taken so that the two standardsare aligned, including having some of the same membersparticipating in both efforts.

One Size Does Not Fit All

NSF’s Bestervelt and Carter highlight the importance ofdistinguishing between the requirements for excipients usedin drug products and those used in other applications.

At ExcipientFest, Bestervelt noted that excipient qualityrequirements vary depending on the source, the supplychain, and the subsequent use of the excipient, but thathigh level GMP principles must be considered (see box atright). “All of this has been developed and put into 363,”she explained.

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Bestervelt also pointed out the different focus of GMPs forexcipients vs. those for active pharmaceutical ingredients(APIs) – another important consideration in the 363standard.

API GMPs, she explained, focus primarily on: ● purity ●absence of impurities, and ● documentation. By contrast,GMPs for excipients should focus primarily on: ●consistent composition ● lack of cross contamination, and● documentation.

At the PDA supply chain conference, Cartercommented on how the quality requirements forexcipients used in foods – and the risk assessmentsthat are performed – differ from those used in drugproducts, and how the NSF-IPEC 363 standardclarifi ed that distinction (see box below).

He pointed out that many times excipient manufacturerssupply both the food and pharma industry and may notunderstand the differing requirements. The logic may bethat if it is good enough for a food product – also regulatedby FDA – then it is good enough for a drug product.

The former IPEC chair explained that the NSF-IPEC 363standard will help excipient manufacturers understand thedifference. “Up front, in order to get certi ed, the excipientmanufacturer has to understand what they are making andwhy they are making it.”

Expert Panel Sheds More Light on 363

A panel discussion at the ExcipientFest conference providedthe opportunity for the experts to provide further insightson the new standard and discuss its signi cance.

The panel included IPEC Europe Chair Frank Milek, a QPat Aug. Hedinger GmbH, IPEA CEO Erwin Silverstein, NSFPartner and past IPEC chair Janeen Skutnik-Wilkinson,CDER’s Wolfgang, Huber’s Carter, and Lubrizol GlobalRegulatory Affairs Manager Meera Raghuram.

The panelists weighed in on how the emerging 363 standard:● builds on the IPEC/PQG GMP Guide ● is compatiblewith FDA expectations and guidances ● levels the excipientplaying eld and helps assess quality culture ● provides forexcipient product quality assessment ● compares with EUstandards and directives ● helps establish best practices forrisk assessment ● relates to GDPs, and ● takes into accountexcipient raw material supply chains.

Skutnik-Wilkinson provided an overview of NSF-IPEC 363, highlighting its global reach and theinternational expertise that has been brought tobear in its development. Carter, in turn, explained

further how it builds on the existing IPEC GMPguide.

Skutnik-Wilkinson left P zer to become a partner at NSF-DBA USA in November 2012, where she is doing trainingand consulting in the pharmaceutical, medical device,and dietary supplement arenas. At P zer and previouslyat Merck, she focused on quality regulatory policy andstandard development, with a particular focus on excipientsand over-the-counter products, and was actively involvedwith ICH, PhRMA, and USP quality and supply chain-related initiatives, as well as those of IPEC.

At the ExcipientFest panel session, Skutnik-Wilkinsonexplained that the 363 standard grew from IPEC’s desireto take its GMP guide “to the next level” and create anauditable standard that would encompass the evolvinginternational pharma quality principles, expertise, and bestpractices.

Two important aspects of the new standard, she explained,are its focus on a robust, effective quality managementsystem, and its aim to help rms understand the qualityculture of an excipient company through risk assessment. “Ifa company does not embrace a quality culture,” she pointedout, it will always “struggle” with GMP compliance.

The standard builds on the IPEC GMP guide, Carter noted,by taking the elements in the guide and making them pointsto consider in performing a risk assessment. It directs the rm to consider the points when determining what it istrying to prevent and how.

CDER’s Wolfgang added that the approach taken by thestandard is compatible with the ICH Q8-10 guidelines, andwill help move excipient manufacturer practices closer tothose used by nished dosage manufacturers.

The experts pointed out that the 363 standardwill “level the playing fi eld” among excipientmanufacturers by providing one common auditingstandard and reducing the number of auditsperformed.

It “creates a very clear set of expectations so that everybodyis on the same page,” Skutnik-Wilkinson pointed out. Atpresent, there are a number of different expectations fromdifferent companies, which are dif cult for suppliersto manage, such that “at the end of the day, nobody’sexpectations are met.”

Having one standard, Carter pointed out, allows suppliersto run the same process for both food and drug companies,and to add “quality consistency requirements” needed

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for drug products and explain and communicate that in acontrolled way to the customers and auditors.

Risk Assessment, EU Perspective, GDPs DrawComment

Also drawing comments from the panel was the re ning ofexpectations for risk assessment in the excipient arena, andhow the EU is engaged in this process.

IPEC Europe’s Milek characterized the focus on excipientquality in Europe as “quite new.” He pointed out that adraft guideline from the European Commission on applyingrisk assessments to excipients used in human medicines wasout for comment between February and April (link providedbelow).

The ve-page European draft guideline directs thepharmaceutical industry to base excipient risk assessmentson: ● the excipient itself – classifying the risk into low,medium, and high based on its use and function, and ● therisk pro le of the excipient manufacturer.

Risk assessments, Silverstein commented, are “going to bequite new to excipient manufacturers,” and must be tailoredto the particular excipient and manufacturer such that onlythe applicable elements of the 363 standard to that particularsituation are applied. Best practice, he said, includes riskidenti cation, analysis, and evaluation, followed by a riskmitigation that should be challenged after being put in placeto ensure it is effective.

Also addressed by the panelists was the importanceof the excipient supply chain – including gooddistribution practices and the quality of rawmaterials used in excipient manufacturing.

CDER’s Wolfgang characterized the distribution systemas “very important” for excipients, and noted that issueswith diversion and tampering that occur with nished drugproduct can also happen with excipients. IPEA’s Silversteincommented that unless the excipient is shipped as a fulltruckload with a tamper-evident seal that is examined uponreceipt, ensuring appropriate distribution of the excipient is“very dif cult.”

Carter also addressed the “less than load” (LTL) concern,noting that sometimes excipients are used in small enoughquantities that shipping full truckloads is not practical.

Regarding the raw materials used for manufacturingexcipients, he asserted that the use of risk managementprinciples should go all the way back to the mine or otheroriginal source where it comes “out of the Earth.” Excipientmanufacturers who are in the business for the “long haul”have a vested interest in doing so, Carter maintained.

DOWNLOAD FROM THE STORY:

• EU draft guidance on risk assessment for excipi- ents used in drug products

KEY AGENCY AND INDUSTRY OFFICIALS WEIGH IN ON NSF-IPEC 363

The following are insights provided by the expert panelists who participated at a session at the IPECExcipientFest conference on the ANSI NSF-IPEC 363 standard and its risk assessment focus. Thesession was moderated by Pharmaceutical Technology Executive Editor Patricia Van Arnum. Thepanelists were: IPEC Europe Chair Frank Milek; IPEA CEO Erwin Silverstein; NSF Partner JaneenSkutnik-Wilkinson; CDER Office of Drug Security, Integrity and Recalls (ODSIR) Associate Directorfor Risk Science, Intelligence and Prioritization Steve Wolfgang; Huber Engineered Materials GlobalQuality Director Dale Carter; and Lubrizol Global Regulatory Affairs Manager Meera Raghuram.

The panelists weighed in on how the emerging 363 standard: ● was developed and why it is signifi-cant ● builds on the IPEC/PQG GMP Guide ● is compatible with FDA expectations and guidances ●levels the excipient playing field and helps assess quality culture ● provides for excipient productquality assessment ● compares with EU standards and directives ● helps establish best practicesfor risk assessment ● relates to GDPs, and ● takes into account excipient raw material supplychains.

Also included are Carter’s remarks at the PDA supply chain workshop held a few weeks later regard-ing use of the same excipients in both foods and drugs and Wolfgang’s “regulators perspective” onNSF 363 given in his keynote presentation at ExcipientFest.

Overview of NSF-IPEC 363 and its Development

Skutnik-Wilkinson: One of the key rationales, as folks here are aware, is that we had the IPEC/PQG GMPs that wererevised in 2006. In the 2008-2009 timeframe, IPEC as an organization decided that we really wanted to evolve theguideline to the next level so that we could possibly have it used and referenced by FDA and by other agencies around

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the world, and really make it into an auditable standard as opposed to a guideline.

At that point we had a discussion with NSF, who is accredited by ANSI to develop American national standards. Wefelt it was an important step forward to create a document that could be used officially as an auditable standard,and would be compliant with OMB circular A119 – which is a guidance to the US government that says if there is astandard in place, in lieu of developing its own standard within an agency of the US government, an agency can referto a consensus-based standard.

We pulled together experts on excipients – not just from the US and not just from industry, but from regulatoryauthorities, public health agencies in Europe and the US, and key industry representatives who worked on not onlythe IPEC-PQG original GMPs, but who have really been involved and knowledgeable about excipients – some for 20,30 or 40-plus years. That was the rationale for doing this.

I think it has been a really great process in terms of getting people together and harmonizing expectations. It isfocused on what is important globally.

In terms of the specifics of the standard, anyone who is familiar with the IPEC guide will notice a lot of the samekey things emphasized, as would people familiar with ICH Q10 or ISO. It is focused on a robust, effective qualitymanagement system. It really helps you understand what a quality culture is within a company.

Whether you are talking about pharmaceuticals, excipients or APIs, if a company does not embrace a quality culture, itis always going to struggle with GMP compliance. Because if people do not understand the importance of quality, theyare never quite going to get there – they are going to be doing things because someone told them to. The standardhelps you assess and look at what the quality culture of a company is by how they approach all the different elementsof a quality management system.

There are expectations for appropriate facilities and controls, what the appropriate documentation is, and for theappropriate personnel and training – this is something that time and time again is very important, not only if you are anexcipient manufacturer, but if you are anywhere throughout the supply chain. This is one of the gaps you can see – ifpeople do not understand what they are doing, why they are doing it, and how it can translate at the end of the day toa patient outcome or impact, it gets very difficult for people to do their jobs well.

Appropriate test methods and controls are also part of the overall process.

It is an auditable standard. It does provide a tool in your overall supplier qualification program. It incorporates all thenecessary elements from ICH Q10 and Q9. Q9 is all about risk assessment and why we are all at this roundtabletoday.

IPEC/PQG GMP Guide Evolution

Carter: The IPEC guideline was just that – a guideline. So in certain sections – such as air handling or utilities orpersonnel protection and gowning – it would give several examples that you might find in several situations. Forexample, it says that if you need a controlled environment, you have to control it. It was written in a way that someonereasonably knowledgeable of what they are doing can look at it and make reasonable decisions, and then put in theprograms and processes.

What the ANSI standard did was to take those examples and translate them into a standard that can be auditedagainst. Rather than get prescriptive and say a firm must always wear hairnets in a manufacturing site – when someof those manufacturing sites are in Texas and they are ten acres of distillation columns outside – how is that hairnetprotecting anything? It got to the point of saying instead that a risk assessment should be done. It took the elementsin the guidance and made them points to consider in the risk assessment….

What this standard does is pre-load the risk assessment by stating the risk question – ‘what are you trying to prevent,and how are you doing that?’ In trying to prevent something, consider these things. It did that throughout all the areasof the standard.

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What it does for the excipient manufacturer is put a little work on them to go from being an IPEC GMP-compliantcompany to a company that can be certified under the ANSI standard. They will have to go back and justify why theydid what they did. The advantage is that, all of a sudden, the company has protected itself from loss of knowledgebecause the generation that may have put these things in and then took early retirement when they decided to lay offhalf the workforce are replaced by people they hired for half-price. Having the risk assessment gives them the abilityto understand the reasons for the programs…. It will give the excipient manufacturers a way to stay the same throughtime and capture that knowledge and not lose it.

Compatibility with FDA Expectations and Guidances

Wolfgang: In terms of pharmaceutical quality systems, I think there is a lot of compatibility between the ICH standards,the approaches they recommend, and ANSI NSF 363. It talks about applying risk-based approaches, establishingquality management systems, and it emphasizes the importance of senior management responsibility, which I thinkis something that, as Janeen was saying, is part of building the quality culture within the organization. Because if thesenior management does not support it, certainly it is not going to be supported throughout the organization.

In terms of the types of practices that we have been trying to encourage finished dosage manufacturers to apply, Ithink we are seeing a lot of progress in terms of building the same types of approaches throughout the pharmaceuticalsupply chain, including excipients.

A Level Playing Field and Quality Culture

Skutnik-Wilkinson: One of the key things is that it creates a level playing field. I think that is very important, notjust for pharmaceutical companies, but also for the excipients, as well. If you have too many different standards andexpectations, at the end of the day nobody’s expectations are met. So it creates a very clear set of expectations sothat everybody is on the same page and we know what is important….

As I said in my opening, it tells you a lot about the quality culture. I think one of the things that we are learning as westart doing some deeper dives into some of the incidents that have happened is that a lot of the reasons we have hadissues is because people have not really understood the quality culture of the organization. If you understand wherethey are on the paradigm of ‘everybody has bought into quality, or quality is just the job of the quality unit,’ that tellsyou a lot about what to look at when you are going in to audit the company. The standard is one of the tools that helpyou do that.

It provides an auditable standard. If I have [a supplier] that I have audited for a couple of years to the IPEC standardand now to 363, I know that I have a good relationship. I know that if there is a change they are calling me up andemailing me and telling me everything that is going on in that space. I have a level of confidence that I do not haveto babysit the company.

If it is a new company and I am going to start doing business with them and I do not know anything about the company,I am going to have to do a lot more work. I am going to have to look at the documentation they are using not onlyinternally to satisfy the standard, but also with their customers. So the standard actually helps to bucket the differentsuppliers [regarding] where they are and what needs to be done with each. So it really helps the pharma firm with itsrisk assessment.

My high-risk customers are not the people I buy the most from, [which] are the companies that I have the most trustand faith in because I know their systems and I know their culture. And then there are the people I just do not havethat relationship with yet. To me, that is what I need to know in terms of where my risks are for patients that are gettingmy product.

Excipient Quality Assessment

Carter: From my perspective, what the standard allows you to do using the risk assessment model is describe whatyou do and justify it is a way so that what you are doing for your food additive customers and all the common partscan stay common. One does not have one little requirement or prescriptive requirement that may not make sense in

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your application, but because it is there, you did something different.

It allows you to run the same, to make the same safe product, and then add to it also some of the quality consistencyrequirements needed for drug products and explain and communicate that in a controlled way with everyone. Nowthat there is a standard out there that will be rallied around, you will not be audited by different standards constantlyfrom the same pharmaceutical industry.

Raghuram: I would like to add to what Dale said and also comment on what Janeen said about the level playingfield. I think from an excipient manufacturer’s perspective, we have always used risk assessment to make informeddecisions. But maybe where the gap has been is that it may not have always been documented. As a relatively newemployee in a new business area in my company, sometimes when I ask why we are doing something, the answer is,‘we have always done it this way. We have done it this way for the past 20 years and it has worked well.’

I think what the standard does is that it forces you to look at the quality performance, the customer requirements, andthe safety of the excipient, and document why you are using certain controls or why you may not need certain controlsin certain places. I think that is a very big advantage to implementing – having a consistent standard to follow.

Comparison with EU Standards and Directives

Milek: We are in a situation in Europe now where the excipient regulations are quite new. A transition period endedearlier this year and the new regulations for excipients initially brought risk assessment on the table to be included inthe determination of the level of GMP to be applied to the excipient suppliers.

What is important to mention is that the paradigm in European regulation is that the responsibility for the safetyof the finished dosage form is with the manufacturing authorization holder, meaning the pharmaceutical company.The pharmaceutical companies are responsible to secure the entire supply chain right from the beginning, includingexcipients, APIs, contract manufacturers, manufacturing processes, etc., until the marketing of the drug.

In addition to the GMP requirements for the finished dosage form manufacturing and the API manufacturing, whichinclude risk management principles, there are guidelines defining what GMP is for manufacturing finished dosageforms and what GMP is for manufacturing APIs.

The new regulation for excipients does not require a specific level on the basis of a specific guideline to follow to meetthe requirements – the expectations of regulations – but through the use of risk management principles to first assessthe risk of a certain excipient supplier or manufacturer before defining a certain level of GMP required by the supplierto the expectation. I think that is a quite new approach in Europe, and of course we will see at the end of the day howthis will be enforced and applied.

I have recently gotten a draft guideline on how the risk assessment should be applied by the pharmaceutical industryfrom the European Commission [“Draft Guidelines on the Formalized Risk Assessment for Ascertaining the AppropriateGood Manufacturing Practice for Excipients of Medicinal Products For Human Use,” released at the beginning ofFebruary for a three-month comment period. Link provided above.] Today [April 30] is the deadline for commentby industry.

I think that probably there will not be significant changes to the draft that came from the commission. The draft requiresthe pharmaceutical industry to base the risk assessment on two major items: to determine the risk of the excipient assuch, and to classify excipients into low, medium, and high risk based on the basis of their use and function; and alsoto determine the risk profile of the excipient manufacturer. That is an interesting point.

When you look at what we will expect in Europe, the risk profile of the excipient manufacturer should take into accountthe quality system certification and accreditation of the excipient manufacturer. That brings together these standardsand the expectation of regulators related to the compliance of excipients.

When we compared the requirements for a risk assessment in the standards like ANSI 363 or EXCiPACT…it is thatrisk assessment should be done by both parties. This means that the risk assessment required in the standard by the

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excipient manufacturer is complemented using the risk-based approach by both the supplier and user of the excipient.Each cannot fulfill their obligations without talking to each other.

The pharmaceutical manufacturer will definitely not be able to determine the risk profile of an excipient manufacturer.On the other hand, following the ANSI or EXCiPACT standard requires the excipient manufacturer to know aboutthe application and the risk of the excipient in the final dosage form. So that brings them together. That means thatthe standard is coming at the right time, from a European perspective, because the standard will be able to answerquestions for both sides.

Also very important is that the regulation and the standard, if the standard is applied, bring both ends of the supplychain together. That has been practiced for a long time in industry, but now it is a prerequisite and it is brought underthe umbrella of patient safety.

Best Practices for Risk Assessment

Silverstein: Risk assessment, I think, is going to be quite new to excipient manufacturers. It seems as though it hasbeen rolled out in the pharmaceutical industry, but they still wrestle with the proper way to deal with it.

I have been involved in looking at risk assessments, and have come to certain conclusions now. I think it is importantto note that there will be an expectation to document risk assessment. This is a very comprehensive standard and itrecognizes that you probably will not run into an excipient manufacturer who has to deal with all the requirements ofNSF 363. So those elements that do not apply to the specific excipient situation or the site of manufacture will haveto have a risk assessment to support the fact that those requirements do not apply. Then you are going to have to dorisk assessments where the standard calls for a risk assessment to decide the level of compliance with those specificrequirements.

There are three elements that I would be looking for in a risk assessment

● First of all, there is identification. You need a good, solid identification statement for the risk, clearly delineatingwhat the scope is. In this portion I would expect you to define the potential harm to the patient if the excipientis exposed to that risk. Dale [Carter], I think, pointed out that there are direct hazards and indirect hazards.Examples of direct hazards are chemical or physical or microbiological contamination by exposure of the excipientto the risk. There are also indirect hazards that may become apparent that can lead to stability failures, ormanufacturing problems at the pharmaceutical manufacturer, or that may lead to drug shortages.

● The second key element is analysis. I would expect that there will be an analysis conducted on the identifiedrisks to determine their probability. The probability can be ranked in terms of perception of high or low or medium,but they can also be classified on a scale of one to three, or even one to ten. Then there will be an assessmentthat will determine the probability of the risk, and a separate assessment of the severity of the risk – what is theimpact if this exposure to the excipient does occur as it relates to the patient and patient safety.

● Finally, there is an evaluation. Now that you have the probability and the severity, you combine the two in afashion that leads to a severity rating for the risk, and that will determine the level of protection that you need toapply.

I thought I would give an example of this: Pest control is expected in probably the vast majority of the excipientmanufacturers, because at some point in the process, often after the starting point of GMP, the excipient is exposed tothe environment. Once there is exposure, there is the potential for an infestation by pests. We are looking at a directhazard – infectious agents that are transmitted by pests. Rodents would be a case in point, and perhaps insects,under certain circumstances.

An indirect presentation of a harm could be through product recall. If you wind up shipping an excipient that hasinsect fragments in it to a pharmaceutical company, you are then going to get a phone call about the recall of the drugproduct that was compounded. And it can lead to a shutdown.

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Now you get into the whole analysis of where to apply the pest control measures. As I said, it is where the excipientis exposed. If you have a product that is manufactured in a totally closed environment, the risk is obviously goingto be very small. In that case, you may not apply any risk control measures at all. But if you package in an openenvironment and there are infectious agents or you are in a region of the country where you can have a lot of rodentactivity or other pests in the area, then the level of control is going to have to be very high.

The final thing I would point out is that after you complete the risk analysis and you are putting control measures inplace, you should challenge the measures to see that they are effective. One way you can do this [is by] looking atcustomer complaints for foreign material.

Relationship to GDPs

Milek: The falsified medicines directive, which covers excipients, is limited to GMPs. GDPs and supply chainspecificities are not mentioned related to excipients. The FMD brings clear requirements for active pharmaceuticalingredients. There will be a GDP guidance available from the European Commission for APIs. But there are nospecific requirements related to GDPs for pharmaceutical excipients.

Of course, in the risk assessment guidelines and in the directive it is mentioned that when the risk of the excipientis determined, the source of the excipient has to be considered. But the examples given in the draft guideline forrisk assessment [consider] sources such as the feedstock of the materials, but not the supply chain between themanufacturing site of the excipient and the pharmaceutical customer. Maybe you can consider that a lack. But at theend of the day, coming back to the European paradigm of pharmaceutical regulation, the full responsibility is with themanufacturing authorization holder and the one who is putting the drug on the market. It would be a shortfall if thepharmaceutical manufacturer did not consider the supply chain between the excipient manufacturer and itself….

Skutnik-Wilkinson: You can have the best quality system at the excipient manufacturer, but if there are no controlsonce it leaves the door, what good is it, really? It is the same expectation and the same core principles whether youare talking about the excipient or the finished drug.

On the food side there is a new initiative, ‘farm to fork.’ And it is looking across the entire distribution chain for food….That is absolutely critical, and it has to exist. We have issues like diversion, and that can happen with excipients, too.We have materials traveling in trucks and trains across the US, and it is very easy for something to go wrong….

Wolfgang: I think it is fair to say that the distribution system is very important when it comes to excipients. Certainlywe have seen this with finished drug products as well – for example, in wholesale distribution, where things can gohaywire. You may have an authorized distributor of record, but then you may also have other parties that can also gettheir hands on excipients or drugs in the supply chain. It certainly would be good to have some oversight in the supplychain to ensure that all the players are following the right practices.

Milek: There is not a very sharp border between manufacturing and distribution activities when we go back to thedefinition of manufacturing in GMPs. Then consider what the supply chain operations look like and what is donewith the material between the original manufacturing site and the user site – you have warehousing operations, andsometimes repackaging and relabeling operations, that are clearly manufacturing. But if you consider excipientmaterials, they have physical properties. With all the warehousing conditions in the global supply chain, it is worthwhileto consider [how they are handled].

Silverstein: I think it is worth remembering that the shipment of excipients from point A to point B is generally on acommon carrier. Unless it is a full truckload, it is going to go by whatever trucking company has been authorized topick it up. You can audit the nodes, but it is very difficult to see the transition from ‘A’ to ‘B.’ That puts the onus on thepharmaceutical company to do an adequate job of confirming the product has not been tampered with prior to beingreceived at its door.

I think that it is worth pointing out that FDA pushed back on the whole notion of tamper-evident seals. If you are notgoing to use a tamper-evident seal on an excipient package, you have to justify why there is not one available. Thereis recognition by the agency that those tamper-evident seals are important. But if the pharmaceutical companies do

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not look for the presence of the proper tamper-evident seal, what is the value?

Excipient Raw Material Supply Chains

Carter: There are two big questions. With regard to the starting materials for excipients, let’s remember that anexcipient that is used in a drug product will be consumed by the patient. A raw material used in excipient manufacturingwill be consumed by the process, go through purification steps, and come out to make a different thing than youstarted with – that is the whole concept of process.

Many excipients are made from crude oil or corn or rocks or sand that start out by being dissolved. That is why wetalk about the point where full GMP begins, because, as it says in Q7, everything comes out of the ground, out of theEarth. We do not create matter or energy. As those move through the process, you move from an industrial processto a more controlled process.

That does not say that certain principles do not apply. If you are doing an animal product, then yes, you need toapply the GMP principles regarding TSE risks, for example. You apply the necessary controls all the way back to thestarting materials. But you do need to recognize that the whole business of chemical manufacturing is taking a lesservalue product that is a commodity product, doing processing and purification, and turning it into a more value-addedproduct….

Through risk management, the appropriate principles should go all the way back to the very mine you are taking thematerial from. Some excipient companies are in business for the long haul. They will survey a site or a mine andknow what they have available for the next 30 or 40 years, and they control that, because they need to….

As far as the supply chain goes, typically companies prefer to ship full truckloads so you can put a seal on it forintegrity. Once you go to a ‘less than load,’ or LTL situation, it is going to be unloaded somewhere in an open area,probably in Columbia, South Carolina, waiting for the next truck. LTL shipments are not a good thing. Unfortunately,some excipients are used in such small amounts in manufacturing that a whole truckload might be a three-year supply.That is a challenge, and hence the need for distributors.

An excipient manufacturer needs a good distributor to partner with. The distributor is the excipient firm’s attachmentto the pharmaceutical customers. They play a very valuable role, and should be supported on both ends, by thesuppliers who give products to distributors and the customers that use the distributor. That is what makes it work.

Excipient Quality for Foods vs. Drug Products

Carter: In ICH Q9, the definition of harm includes everything from food risk assessment – no chemical, biological orphysical things should be present. There should not be anything in that drug that is going to make you sick, otherthan the toxic effect of the active ingredient that is trying to kill the disease. But from the excipient vantage point, theyshould be fairly safe there.

The problem is that the active has to be there and has to do the job. If the excipient quality has an impact so thatthe active is no longer as bioavailable, or is no longer as stable for the time that the manufacturer wanted, or worse,it causes some kind of hyperactivitiy or whatever – anytime the excipient causes something to differ from what theexcipient caused during the clinical trial is not a good thing.

It is not only that – if the excipient causes the drug product to fail, you just filled a bunch of API that you cannot reallyreuse. And if that API is something that is hard to get, then there may be a whole batch of drug that is not on the marketand whole lot of patients that cannot have it anymore to treat their disease.

And that just does not happen with food. If we run out of doughnuts, we will still survive. There won’t be massstarvation. Yes, we will be sad – I am not saying there won’t be great sadness. But the main point is this: If you run outof flu vaccine, people are going have the flu, and it is going to bad for the elderly and some of the young and some ofthe pregnant women. That is not good.

It is important that we recognize that even though we essentially do use a lot of food ingredients and industrial

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ingredients in our drugs, there needs to be special care. The drug product companies understand that. The ones thatreally need to learn it are the incidental excipient manufacturers – the ones that say, ‘well, you can test it to USP anduse it,’ and the ones that have a sales guy out in some little place where they have a little extra market going on sellingthrough a distributor, but the main company, the manufacturer, does not even know that that customer is out there.

So that is the real problem that has to be addressed. That is where the GMP for certification really comes in and hasa lot of power. Because up front, in order to get certified, that excipient manufacturer has to understand what they aremaking and why they are making it. That is an important point.

FDA Perspective On NSF-IPEC 363

Wolfgang: I think that ANSI NSF 363 will pretty much set the standard for an excipient quality management systems-based approach here in the US. It establishes the minimum set of general requirements for a quality managementsystem at an excipient site. It is not necessarily going to cover every single aspect of excipient quality, but it certainlyis an important part in determining whether or not an excipient should even be thought about being used before it isused.

The emphasis on the management of quality risk, I think, is a very good approach here. It keeps the standard frombeing too prescriptive. It enables you to apply science and risk, considering patient safety and drug product qualityand what the risks are, and tailor your approaches depending on what excipient you are making to prevent againstcontamination and mix-ups, and to also ensure that end user requirements are consistently met with a high level ofconsideration of pharmaceutical quality and patient safety.

It also, I think, will provide further assurance of traceability for makers and users. Some of the things that are inthere, for example, are certificates of analysis and having better traceability through the supply chain in terms of thedocumentation. Finally, it will add benefits in terms of the oversight of the supply chain upstream of the excipientmanufacturer.

Some of the limitations are that it is a baseline, so there may be other considerations that will need to be applieddepending on the end user requirements – for example, microbiological controls is something that we all need to thinkabout. Even for non-sterile products I think it is an important consideration.

The other thing that I think we need to start thinking about is how we can improve standards for excipient testing toreduce variation. I think USP standards have some limitations in terms of how far you can go with fully understandingthe excipient composition and characterization.

Looking ahead, I see there that are a lot of parallel global standard development efforts. I think we want to continueto monitor efforts that are taking place in the different parts of the world and seek to have a good set of well-alignedstandards.

We need to assure a readily available, secure supply of high quality medical products – that is a very importantconsideration to have in terms of setting our standards. Some of the things that we can do along those lines include:● qualification of suppliers ● monitoring the suppliers, and ● communication.

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