ARCHIVED - Bilateral Meeting Program with Compressed Gas Association (CGA) - Record of Decisions - April 13, 2007

Agenda

Location: 250 Lanark Avenue, Graham Spry Building, Ottawa (Room 150)

Date: April 13, 2007

Time: 10:00 a.m. to 12:00 p.m.

Participants

Health Canada

Kim Dix, A/Associate Director General, Health Products and Food Branch (HPFB) Inspectorate, Chair
Chad Sheehy, A/Manager, Drug GMP Inspection Unit, HPFB Inspectorate
Johanne Veenstra, Compliance Specialist, Drug GMP Inspection Unit, HPFB Inspectorate
Merry Bujaki, A/Manager, Establishment Licences Unit, HPFB Inspectorate
Jo Roulston, Manager, EL Invoicing Unit, HPFB Inspectorate
Nancy Shadeed, Medical Devices Bureau, Therapeutic Products Directorate (TPD)
Marilyn Schwartz, Director, Submission & Information Policy Division, TPD
Mona Chauhan-Sahota, Submission & Information Policy Division, TPD
Trish Larwill, Cost Recovery Initiative, Assistant Deputy Minister's Office, HPFB
Brigitte Zirger, Director, Bureau of Policy, Science and International Programs, TPD
Alan Viau, Associate Director, Bureau of Pharmaceutical Sciences, TPD
Paul Gustafson, Drug Specialist, Manitoba and Saskatchewan Operational Centre, HPFB Inspectorate (by teleconference)
Sharon Mullin, A/Director, Compliance and Enforcement Coordination Division, HPFB Inspectorate

Compressed Gas Association (CGA)

Patrick Litwin (VitalAire) - Chair, CGA Canadian Medical, Food, and Beverage Gases and Equipment Committee
Bill Beckett (Medigas)
Alice Chen (VitalAire)
Anne La Ferrière (Air Liquide Canada)
Joanne Lekkas (BOC Canada)
Ken Lum (Praxair Canada)
Ron Smart (Medigas)
Amy Park (Compressed Gas Association)
Kim Greenwood (Praxair Canada)
James Wallace (GasPro)

1. Welcome and Introductions

Kim Dix, Co-Chair, called the meeting order and welcomed the participants.

Patrick Litwin thanked the HPFB Inspectorate for providing this opportunity to meet, and to discuss and resolve other pending issues.

2. Review of Agenda

No new items were added to the agenda. The agenda was approved.

3. Review of action items and approval of the Meeting Minutes of October 13, 2006

Minutes were approved as presented.

Action Items - From the Meeting minutes of February 15, 2006:

Item 4.1 Dispensing Liquid Oxygen United States Pharmacopeia (USP) in homecare units at a facility site - Louise Jodoin indicated that a medical gas expert will attend the next bilateral meeting in order to address CGA's enquiry regarding the rationale for finished product testing requirements for each homecare vessel filled at a facility, which would not be required for curbside delivery, when a certificate of analysis is available for the tank from which the homecare vessels are filled in both situations.

Update: Paul Gustafson, Drug Specialist from the Manitoba and Saskatchewan Operational Centre, was present by teleconference during the April 13, 2007, bilateral meeting to address this issue. It was explained the activity conducted when filling a homecare vessel either at the facility or by curbside delivery is considered to be the packaging/labelling of a drug and is subject to Good Manufacturing Practices (GMP) described in Part C Division 2 of the Food and Drug Regulations. Even though the drug may have been tested in accordance with the regulations prior to packaging/labelling, there are additional finished product testing requirements that are required after a drug has been packaged/labelled as specified in C.02.019 (2) of the Food and Drug Regulations. C.02.019 (2) requires the packager/labeller to confirm the identity after the lot or batch is packaged/labelled. It was explained that enforcement discretion is applied in consideration to unique circumstances applicable to the industry as related to curbside delivery that can not be extended to circumstances when packaging/labelling is performed at a facility.
Action item is completed.

Item 4.2 Curbside Filling - HPFB Inspectorate to add the response and rationale with respect to the Drug GMP Committee's decision that curbside filling is considered to be a packaging activity, in the medical gases Q&A document (GMP Interpretation Decision Records for Medical Gases (GUI-0062). Louise Jodoin explained that the GMP Interpretation Decision Records for Medical Gas (GUI-0062) will be revised after the GMP for Medical Gases (GUI-0031) is finalized. The general Q&As have been integrated in GUI-0031 but the specific Q&As will remain in GUI-0062. Furthermore, the format of the Q&A document will change.

Update: Johanne Veenstra confirmed that a request for posting the Medical Gas GMP Q&As was sent on April 11, 2007. The Q&As should be posted within the next week.
Action item is on-going (awaiting posting of the revised Q&As).

Item 4.4 Liquid Nitrogen NF - HPFB Inspectorate to add the following exemption to the medical gases Q&A document (GMP Interpretation Decision Records for Medical Gas (GUI-0062)): When a fabricator/distributor supplies small quantities of liquid nitrogen NF in an unpresssurized open-top dewar for professional use, no additional testing is required provided that the source container has been tested, met appropriate specifications and has been released.

Update: Johanne Veenstra confirmed that a request for posting the Medical Gas GMP Q&As was sent on April 11, 2007. The Q&As should be posted within the next week.
Action item is on-going (awaiting posting of the revised Q&As).

Item 4.6 Drug versus medical devices - CGA should request a meeting again with TPD, noting that the discussion at February 15, 2006 bilateral meeting did not resolve the issues surrounding the approval of gases and gas mixtures used in medical applications, as well as summarising the information regarding medical devices provided by Nancy Shadeed and requesting clarification regarding the process for the Drug Identification number (DIN) and marketing authorisations.

Update: CGA is almost done drafting a letter to TPD but, to avoid confusion, decided to wait pending the results of the discussion on compounding at this bilateral meeting. During discussions at this meeting, it was agreed that CGA and TPD will work together and will address this issue separately from these bilateral meetings.
Action item is completed.

Item 5.1 Ethylene oxide / carbon dioxide mixtures - HPFB Inspectorate to add the following exemption to the medical gases Q&A document (GMP Interpretation Decision Records for Medical Gas (GUI-0062)): Due to the carcinogenic nature of ethylene oxide, an identity test is not required to be performed on mixtures of ethylene oxide/carbon dioxide by the importer if the importer sells the gas mixture "as is in the same container" and does not perform any additional fabricating and/or packaging operations for this gas mixture. A certificate of analysis will be required from the fabricator of the gas mixture.

Update: Johanne Veenstra confirmed that a request for posting the Medical Gas GMP Q&As was sent on April 11, 2007. The Q&As should be posted within the next week.
Action item is on-going (awaiting posting of the revised Q&As).

Item 5.2 Drug Establishment Licence activity - fabricate vs. package - HPFB Inspectorate to add the clarification regarding fabricate vs. package with respect to medical gases, in the medical gases Q&A document (GMP Interpretation Decision Records for Medical Gas (GUI-0062)).

Update: Johanne Veenstra confirmed that a request for posting the Medical Gas GMP Q&As was sent on April 11, 2007. The Q&As should be posted within the next week.
Action item is on-going (awaiting posting of the revised Q&As).

Action Items - From the Meeting minutes of October 13, 2006:

Item 4.1 Compounding issues with respect to medical gases - CGA to complete and submit an Agenda Item Summary for our next bilateral meeting.

Update: CGA completed and submitted an Agenda Item Summary to Brenda Lajeunesse on March 16, 2007.
Action item is completed.

Item 4.2 Drug Establishment Licence requirements for foreign sites - CGA members to send requests to the Inspectorate as soon as possible in order to perform foreign site inspections of medical gas establishments for which GMP evidence is expiring at the end of 2006.

Update: CGA members sent their requests to the Inspectorate shortly after the previous bilateral meeting in October 2006.
Action item is completed.

Item 4.5 Discussion of CGA comments on GUI-0031 - Patrick Litwin to forward incident reports pertaining to safety and quality deficiencies of medical gases that were handled by ambulances and fire departments to Louise Jodoin.

Update: Patrick Litwin indicated that he is still gathering information. Once all the information is obtained, the incidents reports pertaining to safety and quality deficiencies of medical gases that were handled by ambulances and fire departments should be sent to Chad Sheehy.
Action item is ongoing.

Item 4.5 Discussion of CGA comments on GUI-0031 - Johanne Veenstra to add the definition of the term "immediate container" from the Food and Drug Regulations to the glossary of GUI-0031.

Update: The definition of the term "immediate container" from the Food and Drug Regulations was added to the glossary of GUI-0031. The guideline was posted on Health Canada's Compliance and Enforcement website on December 29, 2006.
Action item is completed.

Item 4.5 Discussion of CGA comments on GUI-0031 - Johanne Veenstra to remove the example of protective caps in interpretation 6 under the Equipment section of GUI-0031.

Update: The example of protective caps in interpretation 6 under the Equipment section of GUI-0031 was removed. The guideline was posted on Health Canada's Compliance and Enforcement website on December 29, 2006.
Action item is completed.

4. New Issues

4.1 Compounding

Pat Litwin presented the issue and Amy Park provided some background. At the bilateral meeting on February 15, 2006, HPFB Inspectorate suggested that some of the issues CGA described regarding the approval process for gases in medical applications (drugs vs. medical devices) might be addressed by "compounding". At the bilateral meeting on October 13, 2006, CGA was encouraged to review the draft revised policy document POL-0051, Manufacturing and Compounding Drug Products in Canada, and to submit an Agenda Item Summary for the next bilateral meeting.

CGA has reviewed the draft revised policy document POL-0051, Manufacturing and Compounding Drug Products in Canada, and has determined that the provisions for compounding cannot apply to gases in medical applications as written. As stated in the document:

• a patient-healthcare professional relationship must exist;
• the activity must be regulated and the facility subject to inspection by provincial or territorial regulatory authorities;
• compounding must be done by a licensed healthcare professional (e.g., pharmacist, physician, dentist); and
• a general guiding principle is that compounding is not meant to bypass the federal drug review and approval system.

Fundamental changes in policy would be required in order for this possibly to apply to gases in medical applications.

CGA would like to enquire regarding Health Canada's (TPD) thoughts on how some of the compounding concepts could be applied to medical gases.

Marilyn Schwartz noted that component composition ranges have been accepted for DINs for mixture products. In such cases, the name for the DIN includes only a maximum component value, but the ranges are included in the internal notes for that DIN.

Nancy Shadeed from the Medical Devices Bureau explained that a gas mixture is classified as a medical device if the gas mixture is used solely for calibration purposes in calibrating a medical device. The medical device manufacturer who specifies the gas mixture to be used with the device should apply for the medical device licence for that gas mixture.

Brigitte Zirger from the Bureau of Policy provided some background on the drug versus natural health product issue for oxygen. She confirmed that oxygen is a drug and requires a Drug Identification Number (DIN).

Kim Dix concluded that it would be helpful for industry if Health Canada provided additional guidance to explain when a gas is considered a drug, a medical device, or a natural health product.

Action: Amy Park to provide a copy of the letter from the Classification Committee dated November 2, 1999, and subsequent correspondence, such as the letter that was sent to Omer Boudreau dated December 8, 2005, that pertain to the approval process for medical gas drugs and devices, to Brigitte Zirger.

Action: Brigitte Zirger to develop and provide guidance to industry as to when a gas is considered a drug, a medical device or a natural health product.

Action: Brigitte Zirger to meet with CGA to discuss and resolve the issues pertaining to compounding and approvals for gases in medical applications.

4.2 Foreign site inspections in the U.S.

Pat Litwin presented this issue. From the previous CGA-HPFB Inspectorate bilateral meeting (October 13, 2006), the HPFB Inspectorate confirmed that inspections would be conducted for nine (9) medical gas establishments located in the U.S. to obtain a snapshot of the current situation with the medical gas industry in the USA. During that period, no corporate audit report was accepted as evidence of GMP compliance. Once this blitz of inspections is completed (end of January 2007), the policy document Conditions for Acceptance of Foreign Inspection Reports for Listing Foreign Sites on Canadian Establishment Licences (POL-0013) will be revised as required and relevance of corporate audit reports as GMP evidence will be evaluated. CGA requested an update regarding the results of the U.S. foreign site inspections conducted by the HPFB Inspectorate and the status of the policy document.

Chad Sheehy, A/Manager of the Drug GMP Inspection Unit, explained that between November 2006 and February 2007, the HPFB Inspectorate conducted ten (10) inspections of medical gas establishments located in the U.S. Although observations were noted during these inspections, a GMP compliant rating was assigned to all the establishments. Given these findings, the HPFB Inspectorate will resume reviewing corporate and consultant audit reports for foreign medical gas establishments as evidence of GMP compliance, as described in section 5.3.3 of the policy document, should the information outlined in sections 5.1 and 5.2 not be available. As a reminder, in order to accept corporate and consultant audit reports, the criteria described in section 5.3 must be met. The policy document will be revised shortly to reflect this decision.

Action: Chad Sheehy to revise the policy document "Conditions for Acceptance of Foreign Inspection Reports for Listing Foreign Sites on Canadian Establishment Licences (POL-0013)" to reflect the Inspectorate's decision to review corporate and consultant audit reports for foreign medical gas establishments as evidence of GMP compliance by May/June 2007.

4.3 Foreign sites

Ken Lum from Praxair Canada presented this issue. HPFB Inspectorate's Establishment Licence Unit in Ottawa told a CGA member that if finished medical gases are being imported from a foreign site, that foreign site packaging facility must be listed on the Establishment Licence, as well as the fabrication site that is supplying the bulk component gases to that packaging facility. This requirement could not be found in the Guidance Document on Drug Establishment Licences and Establishment Licensing Fees. Therefore, the desired outcome is that the facility fabricating the component gases (and supplying the foreign site packaging facility) would not have to be listed also as a foreign site on the Establishment Licence.

Merry Bujaki, A/Manager of the Establishment Licence Unit, explained that the guidance document Guidance Document on Drug Establishment Licences and Establishment Licensing Fees was removed from the website a year ago since it required revision and updating. A new guide is under development that will eventually replace the withdrawn version. However, the regulations should always take precedence over any guide. As per C.01A.008 of the Food and Drug Regulations, the licence shall indicate, in the case of an importer, the name and address of each fabricator, packager/labeller, and tester from whom the importer is authorized to obtain the drug; and, the address of each building at which the drug is authorized to be fabricated, packaged/labelled or tested, specifying for each building the category of drugs and whether sterile dosage forms are authorized. Therefore, the foreign packaging facility must be listed on the Establishment Licence, as well as the fabrication site that is supplying the gases to that packaging facility.

4.4 Expiry date requirements for medical gases

Pat Litwin presented this issue. Interpretation 3 in the Records section was amended when the final version of the revised GMP for Medical Gases (GUI-0031) was issued in December 2006. As stated in CGA's letter of February 19, 2007, CGA does not agree with the deletion of the historical interpretation that medical gases do not require an expiration date.

The following interpretation was in the Records section of the GMP for Medical Gases (GUI-0031) issued on June 1, 2000, and in the draft revised GMP for Medical Gases (GUI-0031) issued for comment in May 2006:

3. Section C.02.020 (1)(d) does not apply to medical gases. However, if a firm's written procedures call for an expiration date, then a firm will be expected to follow their procedures and apply an expiration date to the product.

This interpretation was amended as follows when the final version of revised GMP for Medical Gases (GUI-0031) was issued in December 2006:

3. Documentation must be available to support the expiry date of the medical gas. In the case of very stable gases that have been used for a long time and packaged in containers that have also been used for a long time, bibliographic data is sufficient. For gas mixtures, the expiry date should be based on validation studies pertaining to the physical aspects such as the rate of stratification.

This change in interpretation has a significant effect on the industry with no benefit to the patient. It was made despite there being no historic reports of injury or harm and no documented risk to the end user from the use of medical gas that did not carry an expiry date.

It is the industry's position that expiry dates should not apply to medical gases, as stability of the gases and stratification of the gas mixtures are not issues of concern. Under section C.02.030 of the Food and Drug Regulations, the sample requirements in section C.02.025 and the stability requirements in sections C.02.027 and C.02.028 do not apply to medical gases. Expiry dates would typically be based on and supported by stability data.

Moreover, CGA supports the proposed amendment to section C.02.030 of the Food and Drug Regulations, which was published in the Canada Gazette, Part I, on September 30, 2006, to clarify that the expiry date requirements in paragraph C.02.020(1)(d) do not apply to medical gases. As stated in the Regulatory Impact Analysis Statement, "Health Canada has historically favoured the interpretation that paragraph C.02.020(1)(d) does not apply to medical gases. This paragraph has not been included in the provisions listed in section C.02.030 of the Regulations that do not apply to medical gases. Health Canada therefore proposes to amend the Regulations to reflect the interpretation currently applied to medical gases."

The aforementioned proposed regulatory amendment followed a meeting between Health Canada staff and CGA members that took place on November 7, 2003, at the request of Ms. France Dansereau, then Manager, Drug GMP Inspection Unit, for Health Canada's HPFB Inspectorate. At that meeting, CGA members provided information requested by Health Canada, to support the formalisation of certain historical interpretations for medical gases in the regulations, including an exemption with respect to expiry dates.

CGA is correct in that the former text for interpretation 3 under the Records section is in line with the proposed amendments to Division 2, Part C of the Food and Drug Regulations (GMP) that were published in Part I of the Canada Gazette on Saturday, September 30, 2006. The exemption for expiry date of medical gases was to remove the application of C.02.020 (1) (d) requiring evidence establishing the period of time during which the drug in the container in which it is sold will meet the specifications for that drug.

However, the Drug GMP Committee intends to contest this proposed regulatory change for the following reasons:

• There are currently requirements under Division 1 of the Food and Drug Regulations relating to expiration dating (C.01.004).
• It is noted that other regulatory bodies such as the FDA and the EMEA have requirements relating to expiration dates for medical gases.

As a result, there should be appropriate evidence available relating to the expiration of medical gases. Appropriate evidence does not necessarily need to be in the form of formal stability programs as described under C.02.027 and C.02.028 of Part C, Division 2 of the Food and Drug Regulations to which medical gases are exempt but could be based on bibliographic data or other available information.

CGA expressed additional concerns regarding the revised wording of interpretation 3 under the Records section. For example, how can expiry dates apply to bulk tanks, as the tanks are always being refilled? How can expiry dates be determined for co-mingled product? Also, what specific types of data would be accepted by the Inspectorate?

With respect to international requirements, CGA pointed out that they have been working with US FDA for many years regarding a petition filed in 1979 to exempt medical gases from expiration dating. The issues being resolved relate to container integrity. Stability or rates of stratification are not an issue. The EU requirement is that the product must have an expiry date, but no data is required to support the expiry date.

Action: J. Veenstra to add the topic of expiry date requirements for medical gases to the agenda for the next Drug GMP Committee meeting, in order to bring CGA's additional concerns to the attention of the Drug GMP Committee.

4.5 Cost Recovery Initiative

Trish Larwill, ADMO, provided the update on the HPFB Cost Recovery Initiative, which has begun consultations on a revised Cost Recovery Framework which sets fees and associated service standards for the regulation, licensing, and post market surveillance of health products. The revised framework is a key component of the Health Products and Food Branch Blueprint for Renewal, which aims to modernize the Canadian regulatory system and strengthen its position as an internationally recognized regulatory leader. The proposed Cost Recovery Framework will, along with a review of the branch's core funding, serve to ensure stable funding for the regulatory process. The timeline for the new fees to be implemented is early 2008-2009.

The revised Framework aims to help address the funding needs of the branch without unduly burdening regulated industries. As well as meetings with key stakeholders, these consultations include two online components: a set of questions in the Consultation Document related to the proposed Framework and a Business Impact Test (BIT) for affected companies. CGA member companies were encouraged to review the Framework and submit their responses to both the questions and the BIT by May 15, 2007. CGA will be meeting with the Cost Recovery Initiative to discuss the proposal in detail on April 30, 2007, including fee mitigation mechanisms to address remote sites.

5. Next meeting & Adjournment

The next bilateral meeting will be held on October 10, 2007, from 1:00 to 3:00 pm.

The meeting was adjourned at 11:50 am.