RECAP : PSG ANNUAL CONFERENCE 2010
Symposium – Exhibition – Job Fair
"QUALITY IN TODAY'S WORLD"

May 11, 2010

Background

In 2010, the Board of Directors of the Pharmaceutical Sciences Group (PSG) decided to change the official moniker of the organization's annual pharmaceutical symposium, exhibition and job fair from "PSG Update" to "PSG Annual Conference" in order to more accurately reflect the widening approach of this event, now in its 38^th year.

Since the learning process is continuous, PSG hosts this annual event as just one of the many opportunities that it provides for industry professionals to stay in touch with the ever increasing number of regionally and globally significant issues. As in past years, the 2010 edition, PSG Annual Conference 2010: Quality in Today's World, was stacked with excellent speakers, informative presentations and scores of professionals eager to learn more about their fields of endeavour. The 2010 conference was designed for practitioners in the pharmaceutical, medical device, natural health product and veterinary industries where "quality" remains not only a keyword for success but where it is "the" keyword for success.

Given that last year's theme (which centred on "quality challenges") inspired such great interest, PSG's Board of Directors and its Annual Conference Committee envisioned the idea of further exploring the quality focus that must be maintained in the exercise of day-to-day responsibilities as industry professionals. As such, PSG's Annual Conference Committee, chaired by Max Zive, decided that this year's focus on quality would concentrate primarily on the requirements flowing from current and upcoming regulatory changes and implementations.  Consequently, the session on May 11^th at Le Jardin Conference & Event Centre in Woodbridge, Ontario brought together several esteemed representatives of two regulatory bodies, namely Health Canada and the FDA, plus a seasoned professional from the private sector to present their assembled knowledge regarding recent regulatory changes in pharmaceutical and related areas.

It is of note that "Le Jardin" was again praised by this year's conference attendees for its superb accommodation of not only the conference sessions but of also the accompanying trade exhibition and job fair which, despite the general lack of available jobs in the market, once more had many enticing positions on offer for PSG members seeking work. To these members, we wish much success!

During conference breaks and at lunch, attendees had ample opportunity to mingle with friends, speakers and PSG committee members, amongst others. Meanwhile, exhibitors had an additional chance to explain their services and to demonstrate some products being offered to clients and customers. In fact, exhibitors were more than happy to provide information about their services and products to all that attended the event.

Keynote - FDA

The conference's keynote speaker, Aloka Srinivasan, Ph.D., from the FDA's Office of Generic Drugs, Center for Drug Evaluation and Research (CDER) delivered on a topic that nowadays seems to have broad industry appeal, to wit, "FDA's New Quality by Design (QbD) Program for Generic Drugs". ICH guides Q8, Q9 and Q10 were discussed extensively as part of Dr. Srinivasan's presentation and, as understood by all, "pharmaceutical development is a learning process which describes the successes and failures in product development and leads to QbD".

According to Ms. Srinivasan, due to a huge backlog in submission reviews, the Office of Generic Drugs (OGD) decided to take steps to develop a tool to implement the FDA's cGMP concepts and principles for the 21^st Century Initiative for ANDAs. This tool is the Question based Review, or QbR, and it poses three fundamental questions that FDA reviewers evaluate in Module 2 of the submission: (1) Will the product design ensure desired performance? (2) Will the sponsor be able to scale up to commercial size and ensure comparable quality between bio-batches? and (3) Will the sponsor be able to manufacture the product with defined quality parameters over time?

The answers to these questions provide the framework for a risk-based scientific assessment of the quality of the product being reviewed. Dr. Srinivasan noted that where justifications are detailed in QbR-QOS (Quality Overall Summary) they will reduce the number of issues that have to be resolved later by the sponsor. Furthermore, she mentioned several critical points that must be taken into consideration during product development, such as physical description (particle size, shape, etc.) of the drug substances and delineation of the impurity profile, both of which are very important and heavily requested by FDA due to the potential for interference with product stability. Similarly, genotoxic impurities have recently become more of a concern for regulators who are increasingly demanding adequate justification for the presence of these impurities. Ms. Srinivasan also explained that "excipients are not inert" (i.e. lactose, glycerin) and may interfere with product formulations which then lead to allergies. In such cases, studies that prove the compatibility of chosen excipients must be part of product development. Moreover, the creation of systems to control impurities (i.e. residual solvents) is also recommended - with HPLC methods being preferred. Regarding the Quality Target Product Profile (QTPP) for a generic product, it must be equivalent to the profile of its reference product. At this point Ms. Srinivasan raised the fact that sometimes a generic producer will attempt to take a shortcut without knowing why the innovator designed the product in a specific, yet different, way. But, as the case of slow release tablets demonstrates, a generic product can be formulated to have a different release mechanism as long its pharmaceutical and therapeutic equivalence to the reference are proved.

Unfortunately, time ran short for discussion of this vast subject area and Dr. Srinivasan concluded by telling those gathered that "everything that is developed and all studies that are performed must be provided to the authorities". She noted that even failures help reviewers to better understand drug development cycles. In summary, the three fundamental questions posed by QbR can be successfully answered but, to do so, industry must "build quality into its products and not just test them" and it should justify, justify and justify everything. Only this path is assured to lead to the highest quality of product! We heartily thank Dr. Srinivasan for her invaluable insights.

Speakers - Health Canada

The second speaker, Chad Sheehy, Manager at the Ontario Operational Centre of Health Canada's Health Products & Food Branch Inspectorate (HPFBI), provided guidance with respect to evidence required to demonstrate GMP compliance of foreign sites. Mr. Sheehy also introduced several new forms intended to facilitate submissions and requests as well as a new email contact (foreign_site_etranger@hc-sc.gc.ca) created to expedite communication with Health Canada. Questions related to GMP compliance of foreign production sites should be directed to this specific email address.

This presentation introduced attendees to the major changes in POL-0013 which is no longer considered to be a policy but rather is viewed as a guide - GUI-0080. The guide has been expanded to cover importers and sponsors and to clarify its scope which now has two distinct sections. GUI-0080 defines additional requirements for documentation, expiry dates for certification and the terms and conditions necessary for foreign site approval. The guide's scope includes an explanation of the evidence that a sponsor must provide to demonstrate GMP compliance of sites in countries with Mutual Recognition Agreements (MRA) for covered products and activities where the certificates of compliance are exchanged between the regulators. A list of MRA countries was provided with Canada presently having three (3) such partners - the European Union, EEA-EFTA (Iceland, Norway, Switzerland, Liechtenstein) and Australia. [If any doubt exists with respect to MRA applicability, the sponsor should send an email message to the address above.] The expiry dates for GMP compliance were set at December 31^st of each year in order to coincide with those for establishment licenses and certification remains valid for two or three years depending on the particular case.

Mr. Sheehy further detailed the types of evidence needed when a site is not located in an MRA country or when the product or activity is not covered under an existing MRA. This process is much more complicated and the list of essential documentation to support GMP compliance is extensive. For example, it would be necessary to demonstrate that the foreign site has an implemented Quality System and, as a last resort, a Health Canada inspection may be required if the site was not previously inspected and approved by the authorities of an MRA partner country. Alternatively, one could follow the pharmaceutical inspection cooperation scheme (PIC/S). However, this cooperative regulatory relationship has its own specific requirements and its outcomes may vary.

A Consultant/Corporate Audit Report may be accepted on a case-by-case basis however several documents, including the qualifications and experience of the auditors, will need to be produced to justify the use of such an audit. In addition, Health Canada provides a template for the audit report that must be utilized to ensure that the same format is consistently followed.

Prior to wrapping up his presentation, Mr. Sheehy commented that Health Canada does not perform inspections of sites located in Colombia due to safety concerns. He also noted that Health Canada is considering the possibility of posting on its website those foreign companies considered as GMP compliant. Our gratitude goes to Mr. Sheehy for the expert knowledge imparted by him.

The third presentation of the day came from Vincent Tong, also from Health Canada's Ontario Operational Centre. His address highlighted the updates to GUI-0069 - Guidelines for Temperature Control of Drug Products during Storage and Transportation. As explained by him, this guide is now more in line with WHO Good Documentation Practises (GDP) with one of the guide's current objectives being the clarification of its internal regulations. Mr. Tong observed that, as part of this clarification initiative, new definitions have been added and simplified examples have been inserted throughout the guide. Additional requirements are now defined with requisite supportive documentation more precisely spelled out. For example, in order to guarantee safe product storage, low-temperature-controlled environments now require specific and clear procedures inclusive of detailed back-up power plans. With regard to vehicles and equipment used to distribute, store and handle drug products, the new regulations mandate the imposition of strong controls. The same holds true with respect to temperature control during bad weather - even though no definition for extreme temperature is stipulated. Quality assurance agreements between health regulated companies and transportation firms must also be furnished since, in general, when any company deals with an unregulated party, product protection is directed by written agreements with defined rules for storage and shipping.

Controlled drugs require particular care and, although "no products are indestructible", Health Canada's gradual implementation of its updated rules prioritizes the most sensitive products. For this reason, feedback of practical experience garnered by industry is very much appreciated.

GUI-0069 does not yet cover APIs and not all shipments are monitored. However, warehouses are being inspected and companies must provide proof of compliance with temperature control procedures. Mr. Tong also illustrated the relationship between "long term storage" and "label requirements" - the latter being dependant on the former. In fact, proper stability data will determine what needs to be added to the labels.

In conclusion, a few simple words aptly summarize Vincent Tong's allocution, namely, companies must enforce rigorous temperature control procedures and provide all sources of justifications to prove that drug products are stored and transported safely. We greatly appreciate Mr. Tong's contribution to ensuring safety within our collective industries.

Next up on the diverse lineup at PSG Annual Conference 2010 was Kevin Chin. Mr. Chin emanates from the Medical Device Compliance Unit of Health Canada's Ontario Operational Centre. His talk covered four (4) major changes to the Medical Device Inspection Program: (1) No longer making observations; (2) Non-compliances called observations; (3) Risk-rated observations; and (4) Inspection ratings.

As well, Mr. Chin highlighted a fifth noteworthy issue. Medical device companies holding establishment licenses had in the past been exempt from regulatory inspections. But now, these inspections, which examine documentation to assess regulatory compliance, are enforced for all medical device companies. Yet such inspections remain distinguishable from those for drugs and biologics which more broadly examine and assess, not only documentation, but also manufacturing, personnel, premises, etc. However, regulatory inspections by Health Canada have demonstrated that it is the lack of establishment licenses that gives rise to the greatest number of citations for non-compliance of medical device companies.

During inspections, government auditors will continue to make recommendations but observation letters will be discontinued (1^st of the four major changes). Moreover, going forward, non-compliances will be called observations (2^nd of the four major changes). Even so, non-compliances will remain violations of the Food and Drugs Act and Regulations and will still need to be addressed in corrective action plans submitted to Health Canada.

The third major change discussed by Mr. Chin is related to risk rating with risks now numbered as 1, 2 and 3 - where Risk 1 observations represent the highest risk. One example of Risk 1 is where a company falsely attests that it has appropriate procedures in place but inspection subsequently reveals that such procedures do not exist. Risk 2 on the other hand may be observed where, for example, labelling is deficient. And Risk 3 may be identified where, for instance, information is missing from an application for an establishment license.

Concerning inspection ratings (4^th of the four major changes), two possibilities exist: "C" - Compliant and "NC" - Non-Compliant. It was pointed out that just because an inspection is rated as "C" does not mean that observations were not noted. It simply signifies that no major observations were encountered but that corrective action remains necessary for any minor deficiencies that were confronted.

Finally, Kevin Chin explained that inspection ratings, although always subject to some inspector discretion, are dependant on the number of noted observations and the risk associated with each and that implementation of all of the aforementioned changes to medical device inspections is slated for fiscal year 2010/2011. As such, our thanks go to Mr. Chin for his brief overview of the impending changes in this significant area of practise.

Q&A - Health Canada

At this juncture, due to the success of the Q&A session at 2009's conference, a similar opportunity was afforded to participants to interact with the speakers from Health Canada.

However, although several intriguing questions were addressed to the Health Canada representatives, this year's session did not seem to muster the same overwhelming acceptance as last year. Therefore, as an alternative, it may be advantageous to permit attendees at next year's event to ask questions following individual presentations.

Speaker - Private Sector

Just after lunch, Stuart Wright from i3 CanReg took to the floor. Mr. Wright brought to the audience a discussion of some of the real-life issues surrounding GMP inspections and he offered some practical examples of how to prevent common mistakes that could lead a company to an FDA Warning Letter or to a failed inspection. In somewhat humorous fashion Mr. Wright described how to proceed during an introductory meeting with the regulator, how many people should be involved in that gathering and other related issues. Later, with tongue-partly-in-cheek, it was suggested that inspectors love to speak with engineers because engineers will invariably disclose 'everything'. A further piece of wry advice, "The Pregnant Pause", was depicted as nothing more than a pause where the inspector refrains from speaking thereby leaving the industry professional to surmise that something else needs to be said with the result that additional information is volunteered.

Returning to the more serious, Mr. Wright stated that typically an FDA pre-approval inspection is required for a New Drug Application (NDA). Canadian biologics submissions also mandate pre-approval inspections. Whether these inspections are conducted with respect to API producers or drug product suppliers, inspection failures constitute the primary basis for NDA non-approvals. Since API inspections frequently find facilities to be less clean than corresponding inspections of drug product facilities, it is important that the final purification stages of API production are handled as rigorously as for drug products. In the same vein, Mr. Wright noted that companies should not be permitted to migrate their quality assurance programs to "QA-lite". In other words, companies should fully embrace their QA responsibilities and maintain program integrity. Other common failings were also illustrated such as approvals of deficient deviation reports, approvals and document control of SOPs without a critical attitude, and so on. It was pointed out that company representatives need to learn how to handle explanations for deviations. Furthermore, GMP training records, transportation and storage data as well as SOPs need to be in order and available during a GMP inspection.

In the case of Health Canada, the agency will press for more information when an inspection response is not adequate. The FDA instead issues a warning letter which is public, is posted on its website and requires a full response within fifteen days of receipt.

To round out his presentation, Mr. Wright tendered several case studies taken from his professional experience and then concluded by commenting that sometimes the best solution is for a company to seek specialized, external help. For his numerous practical examples and simple, effective solutions, our warm appreciation goes to Mr. Wright.

Closing - FDA

The final speaker of the day was Dr. Robert A. Yetter from the FDA Center for Biologics Evaluation and Research (CBER). Dr. Yetter's discourse both exposed some common problems that prevent first cycle approvals and clarified how to have effective meetings with the FDA.

According to Dr. Yetter, in order to facilitate and arrive at solutions, the U.S. Food and Drug Administration is willing to collaborate with companies that are responsive to issues raised early on. Seventy-one per cent (71%) of major deficiencies are identified during the first pre-submission meeting but sometimes, due to the unwillingness of a sponsor to delay its submission, problems are not resolved at the outset. Often the hope for sponsors is that they will be able to address regulatory and compliance issues during the review period.

Sometimes a company will not agree with the decision or assessment of an FDA reviewer or inspector. In such an event, the FDA has an ombudsman available at each of its offices. However, the advice proffered by Dr. Yetter is that, if a company decides to pursue this direction, it should be very certain about the validity of its position, otherwise serious difficulties may arise. Moreover, for some inexplicable reason, FDA staff believe that applications submitted in the 4^th quarter of a year have lower quality. Consequently, these applications have the lowest rate of first cycle approvals. Could this anomaly be due to FDA workload? We simply don't know.

So what should sponsors do to increase the likelihood that FDA reviewers will be satisfied? Dr. Yetter listed the following tasks: Read the guidelines; find specialized professionals such as consultants to help; drive program imperatives with science, not via marketing; answer FDA requests in a timely manner (communication is key); submit applications only when ready, not when company targets demand it (multiple review cycles are not faster); and, be more proactive in communicating with the FDA. Adherence to these few straightforward tips will surely work to hasten product approval.

For pre-submission meetings, the best advice from Dr. Yetter is to ensure that the background package is complete, focused on the questions and submitted in advance. If the FDA does not receive this package in keeping with its timelines, the pre-submisssion meeting will be cancelled. Critical issues must be clearly explained and new data must not be submitted just before or at this meeting. FDA officials need time to evaluate the information therefore a meeting postponement should be requested if necessary. Importantly, prospective applicants should not forget to follow up after the pre-submission meeting. The FDA issues meeting minutes however companies should prepare their own minutes and, if applicable, notify the FDA about any discrepancies between the two.

To sum up, Dr. Yetter stated that FDA representatives are the best avenue for bringing about fast regulatory approval. So, for delivering a very fitting conclusion to a highly instructive and enjoyable day of learning, we applaud Dr. Robert Yetter.

Conclusion

PSG Annual Conference Committee Chairperson, Max Zive, closed the conference by reminding members, other attendees and the event's speakers that plans for next year's conference are to make it even bigger and better. On that note, and on behalf of the Annual Conference Committee and PSG's Board of Directors,  Mr. Zive ended by remarking that he looked forward to seeing everyone again in May 2011.

From my personal perspective, the invited speakers all brought some surprises and extended information that will be most beneficial. With each passing year, this event has become more and more informative whereas the friendly interaction with colleagues and health authorities always makes it special. So it is with this in mind that I hope to have the pleasure of meeting you, the reader, at PSG Annual Conference 2011! Until then, may all of your submissions be successful!

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Marcela Saad

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MarcM Consulting Canada

www.marcmconsulting.ca