Good manufacturing practices for medical gases (GUI-0031)

Rationale

If you run a medical gas fabricating or packaging establishment:

• having clean work areas allows you to achieve sanitary conditions
• maintaining order helps to prevent mix-up
• controlling airborne and other contaminants protects product integrity

Good building design and continuing maintenance lead to cleanliness, orderliness and prevention of contamination. Regular maintenance is also needed to prevent building decline. The main objective of these efforts is product quality.

Interpretation

1. Locate buildings where medical gases are fabricated or packaged in an environment that presents a minimal risk of causing any contamination of materials or medical gases. Measures taken to protect manufacturing processes will be considered along with location.
2. Make sure your premises are suitable for the operation performed there. Design site layout to avoid mix-ups and prevent contamination. Make sure:
   1. There is enough space for receiving and all production activities.
   2. Working spaces allow the orderly and logical placement of materials and equipment (including parts and tools).
   3. Where physical quarantine areas are used, they are well marked, with access restricted to designated staff. Where electronic quarantine is used, electronic access is restricted to designated staff.
   4. Working areas are well lit.
3. Segregate and designate areas to distinguish:
   1. containers set aside for cleaning, testing or maintenance from containers that have been released for filling
   2. different gases
   3. medical gases from non-medical gases
   4. empty from full containers
   5. quarantined finished medical gases from those available for distribution
4. Clearly identify the content of fixed distribution systems at their outlets.
5. Minimize “dead legs” where circulation may be restricted.
6. Identify pipelines carrying medical gases between areas by colour or by standard markings at suitable intervals. Show direction of flow.
7. Locate air intakes used in the production of medical gas in a way that avoids contamination with waste gases and other pollutants. Make sure filters—especially the ones used to trap desiccants after driers—are of suitable construction, and examined and changed as needed.
8. Separate rest, change, wash-up and toilet facilities from production areas. Make sure they are spacious, well ventilated and allow good sanitary practices.
9. Ensure fabrication and filling areas are well lit.
10. Maintain premises in a good state of repair.
11. Secure premises and vehicles used to store medical gases from unauthorized entry.
12. Store filled cylinders/cryogenic vessels in a way that ensures they will be delivered in a clean state, compatible with the environment where they will be used.

Rationale

These requirements are meant to prevent the contamination of medical gases by:

• other gases
• dust
• foreign materials from the equipment, like:
• rust
• lubricant
• particles

Contamination can be caused by poor maintenance, misuse of equipment, exceeding the capacity of the equipment, and use of worn-out equipment.

Arranging your equipment in an orderly way makes cleaning nearby areas easier and avoids interference with other processing operations. It also minimizes circulation of personnel and optimizes flow of material. To fabricate medical gases of consistent quality, you must make sure your equipment performs the way it is meant to be used.

Interpretation

1. Make sure parts in contact with medical gases are designed, constructed and located in a way that allows cleaning and avoids contamination. Where required, fittings and accessory assemblies are designed for easy dismantling.
2. Make sure tankers and trailers and their equipment (hoses, valves, pumps, etc.) are well constructed and maintained. This includes tankers and trailers owned by a contracting firm.
3. In general, dedicate bulk tanks and tankers to a single and defined quality of gas. You may store or transport medical gases in the same bulk tanks, containers used for intermediate storage, or tankers as the same non-medical gas, if you ensure the quality of the non-medical gas is at least equal to the quality of the medical gas, and you maintain GMP standards. In these cases, you should perform and document quality risk management. You should also have a procedure that describes the measures to be taken when a tanker is returned back into medical gas service (after transporting non-medical gas or after a maintenance operation). This procedure should include analytical testing.
4. Use proper filling and storage equipment for medical gases.
   1. Use materials for product contact surfaces that are non-toxic, non-reactive to medical gases and corrosion-resistant.
   2. Use gas filling equipment that prevents wrong connections.
   3. Containers may be connected either to different valves through an adapter, or to a manifold that is itself connected to different medical gas outlets, if you fully validate and document the procedure to ensure no cross-contamination. Either procedure prevents the possibility of connecting a container to the wrong line.
5. Perform installation and operational qualification on equipment used during the critical steps of fabrication, packaging and testing (including computerized systems). Document equipment qualification. You can find more guidance in the Health Canada document: Validation Guidelines for Pharmaceutical Dosage Forms (GUI-0029).
6. You should only use a common system to supply gas to medical and non-medical gas manifolds if there is a validated way to prevent backflow from the non-medical gas line to the medical gas line.
7. Check and maintain equipment used to fabricate, package/label and test medical gases regularly, including computerized equipment.
   1. Calibrate measuring devices according to a written program.
   2. Avoid using temporary devices for repairs.
   3. Keep records of maintenance and calibration. Ensure a system is in place to support identification of calibration status, and you may use means other than labelling.
   4. Calibrate vacuum gauges used during the essential evacuation of residual gas from high pressure cylinders regularly. At routine intervals, calibrate vacuum gauges to standards established by the National Institute of Standards and Technology or another recognized standard. Follow manufacturer's recommendations for frequency of calibration, or determine intervals based on usage and experience. Check vacuum gauges before use (with no vacuum present) to make sure that the needle on the gauge returns to the "zero." Keep calibration records.
8. Make sure repair and maintenance of equipment (including cleaning and purging) does not adversely affect the quality of medical gases.
   1. Describe in your procedures the measures to be taken after repair and maintenance operations if there are breaches of the system's integrity.
   2. Check for the absence of contaminants before releasing equipment for use.
   3. Maintain records of use and maintenance operations.
9. Protect openings for connections on lines supplying medical gases from contamination.
10. Verify check valves used to prevent contamination at regular intervals, to ensure they work properly.
11. You may use a sampling cylinder, such as a hoke bomb (a stainless steel cylinder with a valve on each end that allows a gaseous product to flow through) to sample gases from a storage bulk tank, if you have validated the process. In particular, you must validate the time it takes to fully purge the cylinder, which provides proof that the cylinder has been fully evacuated.

Rationale

Who you hire is one of the most important element in any medical gases operation. Without the proper staff with a quality mindset and training, it is almost impossible to fabricate, package/label, test or store good quality medical gases.

It is essential that you only hire qualified staff to supervise the fabrication and packaging of medical gases. Making medical gases can be highly technical in nature. It requires constant vigilance, attention to detail and a high degree of competence. The reason many products fail to meet required standards is because of poorly trained staff, or a lack of understanding of the importance of production control.

Senior management should determine and provide adequate and appropriate resources (human, financial, materials, facilities and equipment) to implement and maintain the pharmaceutical quality system and continually improve its effectiveness.

Interpretation

1. If you are a fabricator, the person in charge of your company's quality control department, and the person in charge of your manufacturing department:
   1. must have proper professional or technical qualifications (this may include a respiratory therapist under provincial legislation governing health professionals, or someone qualified by pertinent training)
   2. must have practical experience in their area of responsibility
   3. must directly control and personally supervise on site for each working shift when activities under their control are being conducted
   4. may delegate duties and responsibility (for example, to cover all shifts) to a person who meets the requirements defined under 1.a, while remaining accountable for those duties and responsibility
2. The person in charge of your company's quality control department (whether you are a packager/labeller, tester, importer or distributor of medical gases):
   1. must have proper professional or technical qualifications (this may include a respiratory therapist under provincial legislation governing health professionals, or someone qualified by pertinent training)
   2. must have practical experience in their responsibility area
   3. may delegate their duties and responsibilities to a person who meets the requirements defined under 2.a

3. The person in charge of your filling/packaging operations (including control over printed packaging materials and withdrawal of bulk gases for the purpose of filling):
   1. must be qualified by training and experience
   2. may delegate their duties and responsibilities to a person who meets the requirements defined under 3.a
4. Ensure you have enough staff available on site, with proper qualifications and practical experience appropriate to their responsibilities.
   1. Do not place so many responsibilities on any one individual that quality is put at risk.
   2. Record duties relating to medical gases for all responsible staff in written work descriptions.
   3. Ensure personnel have authority to carry out their responsibilities.
   4. When key personnel are absent, appoint qualified replacements to carry out their duties and functions.
5. Your personnel must be aware of the principles of GMP that affect them. They must receive initial and continuing training relevant to their job responsibilities.
   1. Provide training by qualified personnel. Follow a written training program for all staff involved in fabricating, packaging/labelling, testing, importing, or storing a medical gas (including technical, maintenance and cleaning staff).
   2. Assess the effectiveness of continuing training periodically.
   3. Provide training before implementing new or revised standard operating procedures (SOPs).
   4. Maintain records of training.
   5. Give specific training to personnel working in areas where highly active, toxic, infectious or sensitizing materials are handled.
   6. Review performance of personnel periodically.
6. Make sure any consultants and contractors you hire have the necessary qualifications, training and experience to advise on the subjects for which they are retained. Personnel of subcontractors that could influence the quality of medical gases (for example, personnel in charge maintaining cylinders or valves) should be appropriately trained.

Rationale

Sanitation in a medical gas fabricating and packaging facility, as well as employee quality mindset, influences the quality of medical gases. Medical gases must be fabricated and packaged free from contamination.

A written sanitation program provides some assurance that levels of cleanliness in your facility are maintained and that the provisions of sections 8 and 11 of the Food and Drugs Act are satisfied.

Interpretation

1. Even though medical gases are handled in closed systems, keep areas where medical gases are filled clean and tidy.
2. You must have a written sanitation program available on site for every facility that fabricates or packages/labels a medical gas.
3. Include procedures in your sanitation program that describe:
   1. cleaning requirements for the facility
   2. cleaning requirements for processing equipment
4. Follow written procedures for cleaning critical equipment you use to fabricate, transport, store and fill medical gases. Use written procedures also for cleaning and purging pipelines that carry medical gases. Include checks for the absence of cleaning agents or other contaminants. Validate and document all procedures. This includes tankers and trailers owned by contracting firms.

Rationale

The manufacture of medical gases is carried out in closed equipment. Potential for environmental contamination of the product is minimal.

The hygiene requirements for personnel who help produce medical gases are similar to those for personnel involved with other dosage forms. However, the extent to which they are applied will greatly depend on the operation and the procedures used.

Interpretation

1. Make minimum health requirements available in writing, including:
   1. No person affected by an infectious disease or having open lesions on an exposed surface of the body will engage in the manufacture and packaging of medical gases.
   2. People responsible for performing odour tests do not have ailments that can adversely affect test results.
   3. People responsible for performing inspections involving distinguishing colours can distinguish colours properly.
2. Clearly define clothing requirements and hygiene procedures for company personnel and visitors in your written hygiene program.
   1. People must wear clean clothing and protective covering anywhere a potential for contaminating a medical gas exists.
   2. Operators must avoid direct contact between their hands and any parts of equipment that come in direct contact with the medical gas.
   3. Unsanitary practices are not allowed in processing areas.
   4. Requirements for personal hygiene should be outlined when important to the quality of the product.

Rationale

Testing raw materials before using them has three objectives:

1. Confirm the identity of the raw materials.
2. Provide assurance that the quality of the medical gas in dosage form will not be changed by raw material defects.
3. Confirm that the raw materials have the characteristics that will provide the desired quality in a given manufacturing process.

Interpretation

1. For fabricators, test raw materials to specification prior to use and after you receive them.
2. Make sure your specifications comply with your marketing authorization. Check to see if a monograph exists in a pharmacopeia listed in Schedule B to the Act. If so, make sure your specifications meet the monograph.
3. Validate test methods, and document the results of validation studies. Full validation is not needed for methods included in any standard listed in Schedule B to the Act. But if you use one of these methods, you must establish its suitability under actual conditions of use. Conduct method transfer studies when applicable.

4. You may add deliveries of raw material to a bulk storage tank containing the same gas from previous deliveries. In this case:
   1. You must test a sample of the delivered raw material and find it to be satisfactory.
   2. When the raw material is a single gas accompanied by a Certificate of Analysis, you may take the sample and test it after:
      1. allowing for sufficient mixing of the delivery in the bulk storage tank, and
      2. adequately purging the sampling line
   3. When the raw material is a mixture, your testing must verify each component

Rationale

Section C.02.010 outlines options for when you should carry out testing as per section C.02.009. Buying raw materials is an important operation. You must have in-depth knowledge of the raw materials and their vendor.

Interpretation

1. Prior to use and after receiving the raw material at your facility that fills medical gas into containers, take a sample and perform testing. Conduct specific identity testing on all lots of any raw material (see section C.02.009, interpretation 2). When the raw material is a bulk gas accompanied by a Certificate of Analysis, you may take the sample after allowing for comingling of the delivery in the bulk storage tank.
2. For tests other than identity tests, paragraph C.02.010 (1) (b) outlines conditions you must meet if you rely on test results provided by the vendor.
   1. Evidence satisfactory to the Director should include:
      1. either evidence of ongoing GMP compliance (including process control and validation in accordance with these guidelines), or an audit report issued by a qualified authority (demonstrating that the raw material fabricator complies with the ICH document ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients or with any standard or system of equivalent quality)
      2. an certificate of analysis for all lots, showing actual numerical results and the product specification and validated test methods used
      3. complete confirmatory testing on a minimum of one lot each year of a raw material received from each vendor, with the raw material chosen on a rotational basis
      4. where multiple raw materials are received from the same vendor, confirmatory testing must be carried out for each raw material at least once every five years
   2. If any lot is rejected, the vendor must be requalified.
3. Conditions when transporting and storing raw materials should prevent changes to the potency and purity of the raw material. In order to show that these conditions have been met, you must have standard operating procedures and records for shipping and receiving that contain:
   1. the type of packaging to be used
   2. labelling requirements
   3. mode of transportation
   4. seal of package
   5. verification to ensure that each package has not been tampered with and that there are no damaged containers
   6. evidence that shipping requirements have been met

Rationale

You must take measures to maintain the integrity of a medical gas, from the moment the raw materials or bulk gases enter your plant, to the time you release the finished product for sale and distribution. These measures ensure that all of your manufacturing processes are clearly defined and systematically reviewed in light of experience. They also demonstrate that your manufacturing processes can consistently produce medical gas products that comply with their established specifications for quality.

Interpretation

1. Handle all raw materials, packaging materials, and medical gases according to pre-approved written procedures or instructions. This includes when receiving, quarantining, sampling, storing, tracking, labelling, processing, packaging and distributing. You must keep records as required.
2. Validate all critical production processes. Conduct validation studies according to predefined protocols. Prepare, evaluate, approve and maintain a written report summarizing recorded results and conclusions.
3. Approve changes to production processes, systems or equipment that may affect product quality and/or process reproducibility before implementing them. Where applicable, you should also validate these changes.
4. Avoid any deviation from instructions or procedures. If deviations happen, have qualified personnel investigate and write a report that describes the deviation, the investigation, the rationale for disposition, and any follow-up activities required. Your quality control department must approve the report and maintain records.
5. Store bulk gases under conditions and in distribution systems that prevent product mix-up, deterioration or contamination.
6. Check measuring devices regularly for accuracy and precision. Maintain records of such checks.
7. Make written procedures available on site to ensure that raw materials and bulk gases:
   1. are identified by lot number, receiving number or laboratory control number
   2. are released for production or filling operations according to written procedures approved by the quality control department
   3. meet Schedule B standards (if applicable) and Certificates of Analysis are reviewed and available on site for each lot of source gas received
   4. are stored under conditions that will preserve their quality and avoid their inadvertent use
8. Make written procedures—approved by the quality control department—available to ensure that containers are checked or tested and meet their specifications before being filled.
9. Ensure processing operations are covered by master formulae. These must be prepared by, and subject to independent checks by, people having the qualifications described under section C.02.006.
10. Write master formulae, master production documents and/or master filling documents to ensure 100% of label claim and include:
    1. the name of the product
    2. the name and concentration of components, including acceptable tolerances
    3. the filling sequence of components
    4. the fill pressure or weight of components
    5. in-process and final quality control requirements
11. Before you start any processing operation, take and document all necessary steps to ensure that your work area and equipment are clean. They should be free from any raw materials, medical gases, product residues, labels or documents not required for the current operation.
12. Make sure manufacturing and filling records contain all information related to the manufacturing and filling of each batch of medical gas, including:
    1. in-process quality control requirements
    2. equipment used (if multiple systems are used for same product)
    3. a mark that is unique to the individual, or the initials of personnel involved in the activity
    4. a name for each raw material in a mixture, and references to the relevant specification(s)
13. Include the following in completed manufacturing documents:
    1. appropriate check to ensure the containers have been filled
    2. actual results of the quality checks performed
    3. batch or lot number, receiving number or laboratory control number for each raw material in a mixture
    4. a mark that is unique to the individual, or the initials of personnel involved in the preparation of the mixture
14. You may add deliveries of bulk gas to bulk storage tanks containing the same gas from previous deliveries. In this case, do one of the following:
    1. Test a sample of the delivered bulk gas before adding it to the storage tank and ensure it is satisfactory.
    2. If the bulk gas is a single gas accompanied by a Certificate of Analysis, allow for sufficient mixing of the delivery in the bulk storage tank, then take the sample. You may take the sample from a sampling line or from the first container filled, provided that the sampling, distribution and filling lines have been properly purged before sampling.
    3. If the bulk gas is a mixture, test to verify each component.
15. You may combine residual batches or lots in cryogenic containers or trailers, or add product from the bulk storage tank to the containers or trailers if you perform purity testing after mixing.
16. Make sure your written instructions ensure that:
    1. Your quality control personnel or qualified replacements record their initials in the filling logs.
    2. You assign a lot number for each medical gas, and it appears on each container. You don't have to include the lot number on each bulk transport container, storage tank filled, and container filled at curbside as long as you document traceability.
    3. You control the filling of high pressure cylinders either by mass, or by monitoring the pressure and the temperature on the wall of cylinders. You may verify correct fill by referring to either a temperature/pressure chart or a target mass chart.
    4. During the manifold filling sequences of high pressure non-liquified compressed gases, you perform a heat of compression check on the exterior surface of each cylinder to demonstrate proper filling.
    5. You conduct a leak test on each container during filling. You must use an appropriate method, such as applying leak detection solution to the valve to detect valve packing leaks, safety plug leaks and other valve leaks. You must conduct a second leak test on each container after filling to detect valve outlet leaks. Leak test solutions that can cause corrosion or leave films—such as soap—should not be used.
    6. You properly quarantine filled containers until released by the quality control department.

    Important

    The leak test does not apply to refrigerated or cryogenic liquids.

17. Follow filling as quickly as possible by labelling. If labelling is delayed, take measures to ensure that no mix-ups or mislabelling can occur.
    1. Document and reconcile label withdrawal.
    2. Control labelling operations by 100% verification. Document verifications.
    3. Document labelling operations.
    4. Whenever possible, attach samples of the printed packaging materials used (including specimens bearing the batch number) and any additional overprinting to packaging orders.
18. Label and identify all containers to make their content easy to distinguish. Identify containers using predetermined and well-recorded procedures under the supervision of qualified personnel. You may segregate medical gases by cylinder colour if the personnel involved are well trained. You must have other measures in place to segregate quarantined and released cylinders.
19. After filling, fit cylinder post valves with covers to protect the outlets from contamination.
20. Store materials and medical gas labels used to identify containers in a limited access area, restricted to designated personnel.
21. Destroy outdated or obsolete materials and labels. Record their disposal.
22. Only release medical gases after your quality control department has approved them.
23. Monitor water used for cooling during compression of air for microbial quality when in contact with the medical gas.

Annual product quality review

24. Conduct an annual product quality review (APQR) of all medical gases. Verify the consistency of your existing process and the appropriateness of current specifications for both raw materials and medical gas. Highlight any trends and identify product and process improvements. You should usually conduct and document these reviews annually, taking into account previous reviews. Include at least a review of:
    1. critical in-process controls, finished product testing results, and specifications
    2. all batches that failed to meet established specification(s) and their investigation
    3. all significant deviations or non-conformances, their related investigations, and the effectiveness of corrective and preventative actions taken
    4. all changes carried out to processes, analytical methods, raw materials, packaging materials or critical suppliers
    5. all product quality-related returns, complaints and recalls, and the investigations performed at the time
    6. the adequacy of any other previous product process or equipment corrective actions
    7. the qualification status of relevant equipment used for fabricating and packaging medical gases
    8. agreements (to ensure that they are up to date)
25. Your quality control department should ensure that the annual product quality review is performed in a timely manner and is accurate. If you are a medical gas company that has implemented a uniform Quality Assurance system across all sites (including periodic on-site self-audits of all sites), you can perform one annual product quality review instead of one at each individual site. APQR reports must be available at each site.
26. Where required, you should have an agreement in place between the various parties involved in the annual product quality review (for example, importer and fabricator). This agreement should define each of their responsibilities in producing and assessing the quality review and taking any corrective and preventative actions.
27. Your quality control department should evaluate the results of this review, and assess whether corrective and preventative action or any revalidation should be undertaken. Document reasons for any corrective actions. Complete corrective and preventative actions in a timely and effective manner. You should have procedures for the ongoing management and review of these actions, and review how effective your procedures are during self-inspection.

Rationale

A recall removes from the market a medical gas that either:

• does not conform to the Act or Regulations
• presents a risk to consumer health

Medical gases that have left the premises of a fabricator, packager/labeller, distributor, importer, or wholesaler may end up in a number of locations. Depending on the non-compliance and how serious the health risk is, you may need to recall a product from the market. If you are a fabricator, packager/labeller, distributor, importer, or wholesaler, you are expected to have a mechanism in place to be able to perform a recall to the consumer level if needed. More guidance on recalls can be found in Recall Policy (POL-0016).

This regulation also requires fabricators, packagers/labellers, distributors, importers, and wholesalers to maintain a program of self-inspection. The purpose of self-inspection is to evaluate whether all aspects of production and quality control comply with GMPs. A self-inspection program should be designed to detect any shortcomings in the implementation of GMPs if they occur and recommends corrective actions.

Medical gases offered for sale in Canada—whether they are produced in Canada or imported—must meet the requirements of Part C, Division 2 of the Food and Drug Regulations (the Regulations). If production and analysis are contracted out, they must be correctly defined, agreed upon and controlled to avoid misunderstandings that could result in a product, work or analysis of poor quality. There should be a written agreement between the parties involved, clearly establishing the duties of each party.

Interpretation

1. You must have a written recall system in place to comply with section C.01.051 of the Regulations. It must include the following:
   1. Notify Health Canada of the recall.
   2. Take prompt action to recall a medical gas suspected or known to be defective, according to a pre-determined plan. The procedures to be followed are in writing and known to all concerned.
   3. Identify the person(s) responsible for initiating and co-ordinating all recall activities.
   4. You must be able to carry out your recall procedure at any time, during and outside normal working hours.
   5. Your recall procedure must outline: the way to decide a recall's extent, notify about a recall, and implement a recall.
   6. Your distribution records must enable tracing of medical gases, including any medical gases that are in transit.
   7. Assess and record the progress and effectiveness of a recall at regular intervals, and issue a final report (including a final reconciliation).
   8. Identify recalled medical gases and store them separately in a secure area until their disposition is determined.
   9. Notify all Canadian and foreign establishments involved in the fabrication, distribution, or importation of the recalled medical gas.
2. You must have a self-inspection program appropriate to your establishment's activities. This program must ensure compliance with Part C, Division 2 of the Regulations, as it applies to medical gases.
   1. You must have a comprehensive written procedure that describes the functions of the self-inspection program.
   2. Your self-inspection team must include personnel who are suitably trained and qualified in GMP.
   3. You must carry out periodic self-inspections.
   4. Senior company management must review reports on the findings of the inspections and on corrective actions. Corrective actions are implemented in a timely manner.
3. To ensure compliance of contractors performing fabrication and packaging/labelling:
   1. You must have a written agreement covering the fabrication or packaging/labelling arranged among the parties involved. The agreement must specify the responsibilities of each party relating to the fabrication or packaging/labelling and control of the product.
      1. Technical aspects of the agreement must be drawn up by qualified personnel who are knowledgeable in medical gas technology and GMP.
      2. The agreement permits the distributor or importer to audit the facilities of the contractor.
      3. The agreement clearly describes, as a minimum, who is responsible for:
         • buying, sampling, testing and releasing materials
         • undertaking production, quality and in-process controls
         • validating processes
      4. No subcontracting of any work should occur without written authorization.
      5. The agreement specifies the way in which the distributor or importer's quality control department ensures that each lot or batch has been fabricated and packaged/labelled in compliance with marketing authorization requirements.
      6. The agreement describes the handling of raw materials, packaging materials, in-process medical gas, bulk gas, and finished medical gases if they are rejected.
   2. The contractor's complaint/recall procedures must specify that any records relevant to assessing the quality of a medical gas (in the event of complaints or a suspected defect) are accessible to the distributor or importer.
   3. You must provide the contractor with all information needed to carry out the contracted operations correctly and according to the marketing authorization and any other legal requirements. You must ensure that the contractor is fully aware of any problems associated with the product, work or tests that might pose a hazard to premises, equipment, personnel, other materials or other products.
   4. You are responsible for assessing the continuing competence of the contractor to successfully carry out the work or tests required according to the GMP principles described in these guidelines.
      1. If you are a distributor of medical gases fabricated, packaged/labelled or tested at Canadian sites, you only need to have a copy of the relevant valid Canadian establishment licence held by the Canadian fabricator, packager/labeller or tester.
      2. If you are an importer of bulk gases and medical gases fabricated, packaged/labelled or tested at a foreign site, you must meet the requirements described in Health Canada's document: How to demonstrate foreign building compliance with drug good manufacturing practices (GUI-0080). The foreign site must be listed on your establishment licence.

Rationale

Quality control is the part of GMP concerned with sampling, specifications and testing. It also includes the organization, documentation and release procedures that ensure that the proper tests are actually carried out. This ensures that raw materials and packaging materials are not released for use—and medical gases are not released for sale or supply—until their quality has been judged to be satisfactory.

Quality control is not confined to laboratory operations. It must be incorporated into all activities and decisions concerning the quality of the product.

Manufacturing and quality control personnel share the same goal of assuring that high-quality medical gases are fabricated. But their interest may sometimes conflict in the short run as decisions are made that will affect a company’s output.

In the medical gas industry, quality control is performed by staff in various departments using a matrix organization. For quality control issues, these people are responsible to the individual in charge of quality control. The independence of quality control from fabricating and packaging is considered fundamental. The rationale for the requirement that the quality control department be supervised by qualified personnel is outlined under the section C.02.006.

Interpretation

1. If you are a fabricator, packager/labeller, distributor, importer or wholesaler, you must have a person on site responsible for making decisions about quality control requirements. At locations with two or fewer operations staff available, the manufacturing and quality control person may be the same, as long as:
   1. it is impractical to have distinct organizational units on site
   2. chances of error are eliminated
   3. the reporting relationship is different when the employee performs quality control functions and when they perform fabrication or packaging/labelling activities
   4. the employee is fully aware of his/her dual role, clearly understands responsibilities and line authority, and acts accordingly
2. The quality control department must have true and effective access to equipment and facilities for inspecting and testing.

Rationale

Your quality control department is responsible for approving all raw materials, packaging, materials and finished medical gases. It is very important that adequate controls be exercised by this department in order to guarantee the quality of the end product. To maintain this level of quality, it is also important to examine all returned medical gases.

Interpretation

1. The head of your quality control department (or an authorized alternate) must sign and date all decisions made by the quality control department, pursuant to section C.02.014.
2. Your quality control department must ensure that raw materials, bulk gases and packaging materials are effectively quarantined, sampled, tested and released before being used to fabricate or package/label a medical gas.
3. Evaluate deviations and borderline conformances according to a written procedure. Document the decision and rationale. Where appropriate, conduct trend analysis on batch deviations.
4. Assess any non-conformances, malfunctions or errors (including those related to premises, equipment, sanitation and testing) that may have an impact on the quality and safety of batches pending release or released. Document the rationale.
5. Destroy finished medical gases returned from the market, unless your quality control department determines that their quality is satisfactory. You may consider returned goods for resale only after they have been assessed according to a written procedure. In your assessment, you must consider the reason for the return, the nature of the product, the storage and transportation conditions, the product’s condition and history, and the time elapsed since it was originally sold. Maintain records of any action taken.

Rationale

Medical gas processes must be designed and developed in a way that takes into account GMP requirements. Production procedures and other control operations are independently examined by the quality control department. Proper storage, transportation and distribution of materials and products minimize any risk to their quality.

Complaints are an indicator of problems related to quality. By tracing their causes, you can determine which corrective measures to take, to prevent them from happening again. Having tests carried out by a competent laboratory provides assurance that test results are genuine and accurate.

You must have written agreements for consultants and contract laboratories that describe the education, training, experience and types of services provided, and make agreements available for examination and inspection. You must also maintain records of their activities.

Interpretation

Your quality control department is responsible for the following:

1. The person in charge of your quality control department (or a designated alternate who meets the requirements described under section C.02.006, as applicable to the activity) must sign and date all decisions made pursuant to section C.02.015.
2. You must ensure that guidelines and procedures are in place and implemented for storage and transportation conditions. Filled gas cylinders and home cryogenic vessels should be protected during transportation and delivered to customers in a clean state, compatible with the environment in which they will be used.
3. Tests must be performed by a lab that meets all relevant GMP requirements. Ensure that:
   1. Lab facilities are designed, equipped and maintained to suit the testing and approval (or rejection) of raw materials, medical gases and containers.
   2. The individual in charge of the lab is qualified in accordance with C.02.006, or reports to a person having these qualifications.
   3. There are enough lab personnel who are qualified to carry out the work they undertake.
   4. Lab control equipment and instruments are suited to the testing procedures undertaken. Equipment and records are maintained as per the interpretations under C.02.005.
   5. Computerized systems are validated, and spreadsheets are qualified.
   6. Out of Specification (OOS) test results are investigated to determine the cause of the OOS.
      1. Have procedures in place to describe the steps to be taken as part of the investigation.
      2. In the case of a clearly identified lab or statistical error, you may invalidate the original results and repeat the test. Keep the original results and record an explanation.
      3. When there is no clearly identified lab or statistical error and retesting is performed, specify the number of retests to be performed on the original sample and/or a new sample—and the statistical treatment of the resultant data—in advance in the procedure.
      4. Report all valid test results (both passing and suspect) and consider them in batch release decisions.
      5. If the original OOS result is found to be valid, raise a deviation against the batch and conduct a complete investigation.
   7. Ensure systems and procedures are in place so that lab records are reliable, complete and accurate.
   8. Ensure that all test results that could affect the quality, safety or efficacy of the medical gas are reported, reviewed and assessed appropriately.
4.  Review all complaints and other information about potentially defective medical gases according to written procedures. Record the complaint with all the original details and thoroughly investigate. Take appropriate follow-up action after investigating and evaluating the complaint. Record all decisions and measures taken as a result of the complaint, and reference them to the corresponding batch records. Review complaint records regularly for any indication of specific or recurring problems that need attention.
5. Establish a change control system to provide for ongoing process optimization and a continuing state of control. Your quality control department must document, evaluate and approve all changes, identifying them with the appropriate effective date. Any significant change may require re-validation.

Rationale

Medical gas quality is directly dependent on packaging quality. When a medical gas is presented in an improper container, the entire effort put into manufacturing control is wasted. Packaging materials must be tested or examined to ensure materials are of good quality before being used to package medical gases. Because medical gas containers are returned and reused, inspection and testing becomes even more important.

Interpretation

1. Examine containers carefully against their specifications before filling.
2. For high pressure containers returned for filling, perform checks and tests on every container. These checks and tests should include:
   1. an external examination of valves and containers for dents, arc burns, dings, oil, grease and other signs of external damage that might cause a container to be unacceptable or unsafe for use
   2. a check to determine that old batch labels (with lot numbers and identification) and other damaged labels have been removed

      Important

      You do not need to remove old labels if they are identical to the labels currently used, in good condition, and correct for the product being filled.

   3. venting or blowing down to atmospheric pressure if any gas is present (or inverting and draining the gas)
   4. an odour or sniff test to check for foreign gas or odour, except in cases where this presents a safety hazard (e.g. nitrous oxide or carbon dioxide)
   5. a check to see if the container re-qualification has been conducted as required.
      Each container must be coded (cylinder marking) to show the date of the last requalification:
      1. Steel cylinders must be re-qualified every five years, unless a “*” follows the testing date (meaning the cylinder may be re-qualified every 10 years).
      2. Aluminum cylinders must be re-qualified every five years.
      3. Water used for hydrostatic testing must be at least of drinking water quality.
      4. The interior of cylinders must be visually examined if the valve is removed during periodic requalification (usually when re-qualification is performed).
   6. evacuation of each cylinder (at least to a remaining pressure of 150 millibar), or purging by a suitable method before any medical gas is introduced into the cylinder (data should be available demonstrating the suitability of the evacuation or purge)

      Important

      As an alternative to evacuation, conduct a full analysis of the remaining gas for each cylinder.

3. Perform checks on cryogenic vessels before filling. The required pre-fill checks are usually outlined in the manufacturer’s manual supplied with each cryogenic vessel. At a minimum, you must do:
   • an external vessel check
   • a check of all inlet and outlet connections
   • a label check
4. Examine cryogenic vessels for Transport Canada markings. Ensure that the pressure relief device on the unit is the right kind for its intended use.
5. Make sure your specifications state that each container must be dedicated for a specific type of medical gas and be uniquely identified (for example, using a specific colour) unless a specific change of grade or service procedure is followed.
6. Check gauges on containers that show volume or quantity to ensure proper operation.
7. Quarantine containers failing above checks and tests to prevent their use.
8. Document examination and testing.

   Information

   Specific testing information can be found in Selection and Use of Cylinders, Spheres, Tubes and Other Containers for the Transportation of Dangerous Goods, Class 2 (CAN/CSA B-340).

Rationale

Regulation C.02.017 outlines options for when you may carry out the testing or examination outlined in regulation C.02.016. As with raw materials, buying packaging materials is an important operation that must involve staff who have thorough knowledge of the packaging materials and vendor.

Packaging materials must come only from vendors named in the relevant specification. All aspects of the production and control of packaging materials should be discussed between the manufacturer and vendor. Particular attention should be paid to printed packaging materials. Labels must be examined or tested after receipt on the premises of the person who packages a medical gas.

Interpretation

1. This section applies in the event that your containers are tested at a location other than where the filling takes place.
2. Make sure conditions of transportation and storage prevent changes to the characteristics of the packaging material. To show these conditions have been met, you must have standard operating procedures and records available that contain the following:
   1. the type of packaging to be used
   2. labelling requirements
   3. mode of transportation
   4. the type and seal of package
   5. verification to ensure the package has not been tampered with and there are no damaged containers

Rationale

Finished product tests complement the controls used during manufacturing. As a fabricator, packager/labeller, distributor and/or importer, you must have acceptable specifications and test methods. This helps ensure that all medical gases sold are safe and meet applicable standards.

Interpretation

1. The person in charge of your quality control department must approve any written specifications (or a designated alternate who meets the requirements described in section C.02.006).
   1. Written specifications must include:
      1. a description of the medical gas, including all properties and qualities (such as identity, purity and potency)
      2. tolerances, and a description of all tests or analyses used to measure compliance with the established tolerances (in enough detail to allow qualified staff to perform them)
      3. the name or identification mark that will be used for each medical gas throughout the processing operation
   2. Specifications must be equal to or exceed a recognized standard, as listed in Schedule B to the Act. They must also comply with your marketing authorization.
2. You must validate test methods, and document the results. You should conduct method transfer studies when needed.

   Information

   You can find guidance for validating particular types of methods in the International Conference on Harmonization (ICH) document Q2 Validation of Analytical Procedures: Text and Methodology, or in any standard listed in Schedule B to the Act.
3. You must test each medical gas to ensure it meets its specifications. You must record test results in a proper document, clearly and concisely.
   1. For a given filling operation of a single gas, you must test a representative number of containers to specification (usually one filled container from each manifold filling sequence).
   2. For high pressure containers filled individually and manually, you must test one filled container per uninterrupted filling sequence. If the filling sequence is interrupted, you must perform additional testing.
   3. For mixtures of two gases, you must test every cylinder to its specification for one gas. Then you must also perform an identity test for the other gas on one cylinder from the manifold filling sequence.
   4. For mixtures containing more than two gases, you should test every cylinder to specification for all but one of the gases. Then you should test one cylinder from each manifold filling sequence for the identity of the remaining gas.
   5. For a mixture of two or more gases first filled into a series of storage buffer tanks, if the mixing process of the gases can be validated to show that the mixture remains homogenous within the buffer tanks and during the filling process, you may perform full testing on one cylinder per filling sequence or manifold.
4. You do not have to analyze vessels filled at curbside if a certificate of analysis is available for the medical gas in the tank used to make the delivery.
5. For deliveries of liquid nitrogen NF in an unpressurized open-top Dewar, you do not need to perform additional testing if the source container was tested, met appropriate specifications and was released. A certificate of analysis must be available for the bulk tank used to make the delivery.
6. When filling homecare units with liquid oxygen USP on company premises, if a certificate of analysis is available for the source container, you only need to conduct identity testing.
7. Ethylene oxide is carcinogenic. So as an importer, you do not need to perform an identity test on any medical gas mixtures of ethylene oxide, as long as you sell the gas mixture "as is, in the same container" and do not perform any other fabricating and/or packaging operations for this gas mixture. You must get a certificate of analysis from the fabricator of the gas mixture.
8. You must quarantine any lot or batch of medical gas that does not comply with specifications. Do not make it available for sale while waiting for final disposal.

Rationale

C.02.019 outlines conditions and exemptions for when you must perform finished product testing. Paragraph C.02.019(1)(b) outlines requirements you must meet as a packager/labeller, distributor or importer of medical gas if testing is done before receipt on your site. Paragraphs C.02.019(3) and C.02.019(4) outline exemptions to finished product testing.

Interpretation

1. If you are a distributor (C.01A.003 (b)) or importer of a medical gas, you must perform testing on a sample taken after you receive it on your site, unless you choose to rely on test results provided by the supplier.

Sites holding a Canadian establishment licence

2. If you are a distributor of medical gases that are fabricated, packaged/labelled and tested at Canadian sites, you only need to have a copy of the authentic certificate of analysis from the licensed Canadian establishment to show you comply with specifications. This certificate must show actual numerical results and refer to the product specifications and test methods used. Retesting, including identity testing, is not required.

Buildings recognized by a regulatory authority in an MRA country

3. If you are an importer of medical gases fabricated, packaged/labelled and tested at recognized buildings authorized by a Regulatory Authority (as listed in section C.01A.019 and identified on your establishment licence), you only need to have a batch certificate for each lot or batch of the medical gas received to show you comply with specifications. The batch certificate must be in the format agreed on by Mutual Recognition Agreement (MRA) partners. Re-testing, including identity testing, is not required when the medical gas is fabricated, packaged/labelled and tested in an MRA country.

Sites in non-MRA countries

4. As an importer, you must meet the following conditions for testing (other than identity testing) if you choose to rely on test results provided by an establishment in a non-MRA country:
   1. You must provide evidence of ongoing GMP compliance, according to a system described in the interpretation of section C.02.012. This can be indicated by ensuring the site is listed on your establishment licence. For more information, please see How to demonstrate foreign building compliance with drug good manufacturing practices (GUI-0080).
   2. Each lot must come with an authentic certificate of analysis, or a copy of it (an electronic copy with an electronic signature is fine). The certificate of analysis must show actual numerical results and refer to the product specifications and test methods used.
   3. You must perform complete confirmatory testing on at least one lot per year per fabricator. You must choose medical gases on a rotational basis.
   4. You may release for sale a lot or batch of a finished product undergoing periodic confirmatory testing before all tests are complete, as long as a specific identity test is performed and your quality control department approves.
5. If any product from a non-MRA site fails to conform to finished product testing requirements, you must conduct an investigation of the extent of the non-compliance. This may include:
   1. re-evaluation of GMP compliance
   2. additional complete confirmatory testing, based on the risk associated with the non-compliance
6. As an importer, you must carry out positive identification on a sample of each lot or batch in a shipment of medical gas that arrives on your site. Acceptable identity test methods could include chemical testing or physical testing (in cases where the product has unique identifiers). Unique identifier principles can be used for labeled dedicated bulk tanks of imported medical gas if the following criteria are met:
   1. Ensure the foreign site is listed on your Drug Establishment Licence.
   2. Use only labeled dedicated bulk tanks with traceability identification. An attestation must be available to declare tank dedication.
   3. Ensure that:
      1. you verify the certificate of analysis and certificate of manufacture before Quality Control review for release to customer
      2. the foreign supplier is qualified by a vendor certification program
      3. periodic confirmatory testing is performed

Rationale (C.02.020 to C.02.024.1)

Good documentation is a key part of any quality assurance system. GMP documentation aims to define the specifications for all materials and methods of fabrication, packaging/labelling and control. This ensures authorized staff have all the information they need to decide whether or not to release a lot of a medical gas for sale. It also provides an audit trail that will allow investigation of the history of any lot or batch suspected to be defective.

Developing good record systems allows you to maintain evidence that medical gases have been produced and packaged/labelled under proper conditions. For medical gases imported from another country, information and evidence must show they are produced and packaged/labelled as carefully as those in Canada are required. Documentation may exist in a variety of forms, including paper-based, electronic or photographic media. The various types and documents used should be fully defined in the pharmaceutical quality system. Records must be reliable, complete, accurate and consistent.

Interpretation (C.02.020 to C.02.024.1)

1. For all sections of the GMP guidelines, you must keep standard operating procedures (SOPs) for reference and inspection. These SOPs must be regularly reviewed and kept up to date by qualified staff. You must document reasons for any revisions. You should have a system in place to ensure that only current SOPs are in use. Where needed, keep records of SOPs for all computer and automated systems as well.
2. Your quality control department must approve, sign and date all relevant SOPs and GMP documents (such as records of actions taken or conclusions reached). They must also approve any changes to these documents by signing and dating the change. All changes must also be signed and dated by the person making the change. Any change should still allow the original information to be read. Where appropriate, record the reason for the change.
3. You may maintain records in electronic format as long as you also keep backup copies. Electronic data must be easy to print. Your records must be secured and you must be able to provide them within 48 hours.
4. You may use an electronic signature instead of a handwritten signature. But this system must be evaluated and tested for security, validity and reliability. You must keep records of those evaluations and tests, and document validation of electronic signature identification systems.
5. You must provide any documentation for evaluation by Health Canada in one of Canada's official languages (French or English).
6. Your records must include a copy of master filling and/or master production documents that are verified, dated and signed. All the steps of the process required by the defined procedures and instructions must be documented, as it is performed. However, instead of repeating in detail each operation in the manufacturing orders, you may refer to the master filling documents that contain these details.
7. Section C.02.020 applies only to fabricators, packagers/labellers, distributors referred to in paragraph C.01A.003(b), and importers to the extent that they perform operations on a medical gas.
8. You must have documentation to support the expiry date of a medical gas. For 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 enough. For gas mixtures, the expiry date should be based on validation studies related to physical aspects (such as the rate of stratification).
9. The following documents must be maintained by the fabricator, packager/labeller, wholesaler, distributor (C.01A.003) and importer of a medical gas, as they relate to operations in Canada:
   1. distribution records for all sales of medical gas, including professional samples (records must be easily accessible to allow a complete and rapid recall of any lot or batch of a medical gas, but you do not have to track by lot number)
   2. records of complaints or other information you receive relating to quality, deficiencies or hazards of a medical gas, and any follow-up investigations and corrective actions taken
   3. records of the results of your self-inspection program, and any actions taken
10. The fabricator of medical gas mixtures must maintain these documents:
    1. written specifications for the raw materials
    2. results of the raw material testing
    3. sources of the raw materials supplied
11. The packager/labeller must maintain these documents:
    1. written specifications for the packaging materials
    2. results of the packaging material examinations or testing
    3. sources of the packaging materials supplied
    4. documentation for cylinders and valves that include:
       • certification issued according to Transport Canada's requirements for new cylinders
       • written specifications that outline the checks to be performed on empty cylinders and valves before filling and other requirements.
       • checks for functionality on valves on cylinders
       • records of any checks
12. The fabricator and packager of medical gases must maintain records about the operation of the sanitation program required under section C.02.007.
13. You must generally retain records required under sections C.02.021(1), C.02.022 and C.02.023 for at least one year past the expiration date of the medical gas. For medical gases that do not require an expiration date, you must retain records required under sections C.02.021(1), C.02.022 and C.02.023 for at least five years from the date of fabrication or packaging/labelling. Gas chromatogram charts are considered to be records/evidence of testing and must be maintained for five years from the date of filling.
14. You must maintain records detailing the qualifications/experience of any consultant employed for GMP purposes, along with the services that each consultant provides.
15. Maintain records of all personnel employed in GMP activities, including:
    1. organization charts
    2. each person's title, job description, responsibilities, qualifications, experience and training
    3. the name(s) of each person's designated alternate(s)