Good Manufacturing Practices Questions and Answers
Health Canada / Health Products and Food Branch Inspectorate
Premises - C.02.004
Q. 1 Are firms required to use high-efficiency particulate air (HEPA) filters for air supply in areas used for the manufacture of non-sterile dosage forms?
A.1 Division 2, Good Manufacturing Practices (GMP), of the Food and Drug Regulations does not specifically require manufacturing facilities for non-sterile drugs to maintain HEPA filtered air.
The Regulations do require the use of equipment for adequate control over air pressure, microorganisms, dust, humidity and temperature, when appropriate. In addition, this section calls for use of air filtration systems, including prefilters and particulate matter air filters on air supplies to production areas, as appropriate. These provisions speak to measures to prevent cross contamination, and the key phrase is “when appropriate”.
Despite the lack of an explicit GMP requirement, some firms may elect to use HEPA filtered air systems as part of their dust control procedures. For example, firms may perform dust containment assessments and decide that such filters are warranted to prevent cross contamination of highly potent drugs that, even in small quantities, could pose a significant health hazard when carried over into other products.
Q.2 Is there an acceptable substitute for dioctyl phtalate (DOP) to integrity testing of high-efficiency particulate air (HEPA) filters?
A.2 Yes. Dioctyl phthalate aerosols also called Di (2-ethylhexyl) phthalate, di-sec octyl phthalate, DOP, or DEHP, have long been used to test the integrity of HEPA filters but concern about the potential health effects to people working with DOP test aerosols has led to a search for a safer equivalent replacement.
The product of choice from US Army testing with assistance from various private companies was a Henkel Corporation (Emery Group) product called Emery 3004 PAO. This product is a polyalphaolefin (POA) in the 4 centistoke (4 cSt) viscosity grade, used primarily as a lubricant base stock for oils, lubricants, and electrical/hydraulic fluids.
Emery 3004 (POA) can replace DOP in HEPA integrity testing.
Q.3 What is the acceptable limit for dew point of the compressed air used in pneumatic equipment and to dry the manufacturing tanks after cleaning?
A.3 Under the “Good Manufacturing Practices Guidelines, 2009 Edition (GUI-0001)” (http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/gui-0001-eng.php), there is no limit for the relative humidity % of the air used for pneumatic equipment and to dry manufacturing tanks. From a general perspective, based on Interpretation 4 under Section C.02.004 Premises, the humidity must be controlled where required to safeguard sensitive materials. Consequently, it is the fabricator, packager/labeller’s responsibility to establish the pertinence of such control. If the humidity % of the compressed air used at the last step of drying of a reservoir is too high, micro-droplets of water could be generated on the internal surfaces by condensation, hence contributing to the possibility of microbial growth following storage.
Similarly, it is important to make sure that residual water has been completely eliminated from hard to reach surfaces of the equipment after cleaning operations.
Q.4 What are the requirements applicable to Quality Control (QC) and engineering personnel who travel many times daily between self-contained facilities and the regular facilities?
A.4 Movement of personnel between self-contained and other facilities must be subject to procedures that will prevent cross-contamination. This may include but is not limited to decontamination procedures such as showering and change of clothes.
Q.5 What should be the standard of compressed air used in the manufacture of a drug?
A.5 Air that comes into direct contact with primary contact surfaces and/or the product should be monitored to control the level of particulates, microbial contamination, and the absence of hydrocarbons. Limits used should take into consideration the stage of manufacture, product, etc. Additional tests might be required due to the nature of the product. Gas used in aseptic processes must be sterile and filters checked for integrity.
Q.6 Does the concept of self-contained facilities apply equally to research and development laboratories (susceptible to contain highly sensitizing, highly potent or potentially pathogenic material in the analytical scale) that may be in the same building as the manufacturing facilities, or is this concept limited to actual manufacturing operations?
A.6 It is the responsibility of the manufacturer to ensure that their premises and operations have been designed in such a manner that the risk of contamination between products is minimized. This would include research and development areas within facilities where marketed drug products are fabricated and packaged.
Further guidance can be found under Interpretation 11, Section C.02.004 Premises of the “Good Manufacturing Practices Guidelines, 2009 Edition (GUI-0001)” (http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/gui-0001-eng.php).