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GMP Questions and Answers

 

The GMP questions and answers (Q&A) presented below were previously found in the document entitled "GMP Interpretation Decision Records - 2003 Edition". This Q&A list will be updated on a regular basis. Note that the date at the end of each Q&A represents the date on which the Q&A was added to the list.


PREMISES - C.02.004

Q. 1 Are firms required to use HEPA filters in the manufacture of non-sterile dosage forms?

A.1 The GMP regulations do not specifically require manufacturing facilities for non-sterile drugs to maintain high-efficiency particulate air (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. (September 9, 2003)

Q.2 Is there an acceptable substitute for dioctyl phtalate (DOP) to integrity testing of 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 high efficiency particulate air (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. (September 9, 2003)

Q.3 A firm uses a dedicated suite for the manufacturing of antineoplastics which is under negative pressure to the rest of the facility and has the air vented to the outside; the equipment, however is not dedicated. Is this arrangement acceptable?

A.3 According to the 2002 edition of the GMP Guidelines, under Premises C.02.004, interpretation 11, self-contained facilities should be used for the production of certain biological and cytotoxic drugs. Under this interpretation, a self-contained facility is a facility which provides total separation of all aspects of the operation, including equipment movement. Although not an absolute requirement, dedicated equipment for the manufacture of certain cytotoxic drugs is highly recommended. However, use of non-dedicated equipment may be acceptable under certain circumstances, depending on the nature of the antineoplastics produced, but it must be supported by properly validated cleaning and decontamination procedures. (September 9, 2003)

Q.4 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.4 Under the GMP guidelines, 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 "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. (September 9, 2003)

Q.5 What are the requirements applicable to QC and engineering personnel who travel many times daily between self-contained facilities and the regular facilities?

A.5 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. (September 9, 2003)

Q.6 In Interpretation 11.2 under Premises, a reference is made to "campaign production". However, this term is not defined in the glossary of the GMPs. Could you elaborate more on this approach of manufacturing.

A.6 The following definition is included in the Annex for Schedule D Drugs - Part 1 and should be used: "Sequential processing of material, either more than one product in a multi-product facility or more than one lot of the same product in a dedicated facility, over a defined period of time. Campaign production could occur at any point in a production process where common rooms/suites and/or equipment are reused for multiple products/lots."

This definition will be included in the subsequent revision of the GMP Guidelines. (September 9, 2003)

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EQUIPMENT - C.02.005

Q. 1 Should equipment be labelled with calibration dates?

A.1 Major equipment should be identified with a distinctive number or code that is recorded in batch records. This identification requirement is intended to help document which pieces of equipment were used to make which batches of drug product.

The GMP regulations do not require that each piece of equipment bear status labelling as to its state of calibration or maintenance. However, equipment must be calibrated and/or maintained according to an established schedule, and records must be kept documenting such activities.

The regulations do not distinguish critical from non-critical equipment for calibration and maintenance purposes. However, the need for calibrating a given piece of equipment depends on its function. In general, equipment that measure materials warrant calibration. Equipment not requiring calibration/maintenance need not be tracked or included in the firm's calibration/maintenance program, but the firm must be able to support its decision to exclude a particular piece of equipment from the calibration/maintenance program.

During an inspection a firm should be able to document when a specific piece of equipment was last calibrated/maintained, the results or action, and when its next calibration/maintenance is scheduled. The absence of such documentation is considered a GMP deviation. While the absence of a calibration/maintenance tag is not objectionable, the presence of a calibration/maintenance tag alone should not be assumed to satisfy regulatory demands, and the supporting documentation should be audited. The firm should also be able to support its decision to not include a particular piece of equipment in the calibration/maintenance program. (September 9, 2003)

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PERSONNEL - C.02.006 Updated

Q.1 Can you expand on the delegation of authority for the person in charge of QC and manufacturing departments for a fabricator, packager/labeller or tester of drugs?

A.1 According to Interpretation 1.1 under C.02.006, the only two persons that are required to hold a university degree for a drug fabricator, packager/labeller or tester are the person in charge of the manufacturing department and of the QC department. Specific tasks are required by the GMP regulations to be performed by one of these two persons. However, the Inspectorate acknowledges the fact that this may represent a workload that is impossible to carry for one person. In line with interpretation 1.4, those tasks can be delegated to a person in possession of a diploma, certificate or other evidence of formal qualifications awarded on completion of a course of study at a university, college or technical institute in a science related to the work being carried out combined with at least two years relevant practical experience. The person in charge remains, however, accountable for the tasks delegated and retains the necessary authority. (September 9, 2003)

Q. 2 Is a company required to notify the Inspectorate of a change in key personnel, such as the person in charge of QC or manufacturing department?

A.2 No. However, it is the company's responsibility to make sure that the new person meets the requirements of interpretation 1 or 3 under C.02.006, depending on the activities performed. (September 9, 2003)

Q.3 With respect to Interpretation 1.1 of Section C.02.006 what is meant by a university degree or equivalent? Updated

A.3 Under this interpretation, the individuals in charge of the manufacturing department and the quality control department for a fabricator, packager/labeller and tester must hold a Canadian university degree or recognized as equivalent by a Canadian university or Canadian accreditation body in a science related to the work being carried out. (May 12, 2006)

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SANITATION - C.02.007 & C.02.008

Q.1 Is fumigation a requirement under sanitation?

A.1 The written sanitation program should include procedures for pest control as well as precautions required to prevent contamination of a drug when fumigating agents are used.

Fumigation is not a requirement per se. Infestation should be monitored and controlled. Where fumigation is used, appropriate precautions should be taken.

Methods of sanitary control that satisfy the requirements of Sections 8 and 11 of the Food and Drugs Act would be considered to be acceptable. (September 9, 2003)

Q.2 What limits are acceptable on product residues regarding sanitation?

A.2 Guidance for the establishment of limits can be obtained from theCleaning Validation Guidelines available on the Health Canada's Compliance and Enforcement website. (September 9, 2003)

Q.3 Should individuals who are known carriers of communicable disease be allowed to work in production areas?

A.3 Under Section C.02.008 of the GMP regulations a person who is a carrier of a disease in a communicable form should not have access to any area where a drug is exposed. The likelihood of disease transmission by means of a drug product would depend on the nature of the disease and the type of work the employee carries out. It may be advisable to consult with a physician. Certain diseases could be transmitted through a drug product if proper hygiene procedures are not followed by an infected employee handling the product. However, an employee may also be a carrier of a communicable disease and not be aware of it. Therefore, in addition to strict personal hygiene procedures, systems should be in place to provide an effective barrier that would preclude contamination of the product. These procedures must be followed at all times by all employees. (September 9, 2003)

Q.4 Are gowning rooms required even in pilot plant operations?

A.4 Even in a pilot plant consisting of a small laminar flow area where the apparatus for filter sterilization of solutions are set up, it is an unacceptable practice to gown in there. A change room should be available besides their sterile pilot plant production area.

Based on the assumption that the pilot plant will produce drugs for sale - including clinical studies - then the same principles and considerations that apply to full scale production operations must also be utilized in pilot plant facilities. (September 9, 2003)

Q.5 What are considered as being acceptable limits for cross-contamination when performing cleaning validation?

A.5 Contamination may include not only carry over from a previous product or residual cleaning solvents, but also detergents and surfactants.

No established standard acceptance limits for cleaning validation exist. Due to the wide variation in both equipment and products produced, it would be unrealistic for a regulatory body to determine a specific limit.

However, firms need to establish limits that reflect the practical capability of their cleaning processes, as well as the specificity of the analytical test method.

When determining the acceptance limit, relevant factors generally include: (1) Evaluation of the therapeutic dose carryover; (2) toxicity of the potential contaminant; (3) concentration of the contaminant in rinse and swab samples; (4) limit of detection of the analytical test method; and, (5) visual examination.

Guidance for the establishment of limits can be obtained from theCleaning Validation Guideline available on the Health Canada's Compliance and Enforcement website. (September 9, 2003)

Q.6 In terms of cleaning, what would be the frequency and type of cleaning for equipment and premises for successive manufacturing of batches of the same product? And for different strengths of the same product?

A.6 Interpretation 3.5 under C.02.007 specifies that "a cleaning procedure requiring complete product removal may not be necessary between batches of the same drug". The frequency and type of cleaning for equipment and premises must address the length of time between consecutive lots with the ultimate goal that a particular lot won't be contaminated by the previous lot or the environment. It must also ensure that residual quantities of the previous lot won't impact on the quality of the following lot. Thus, a partial cleaning would be required between two lots of the same product, especially for forms such as liquids or suspensions, in order to prevent a few units at the beginning of a new lot from being filled with residual quantifies from the previous lot that may be located in packaging equipment such as hoses or pistons. It would be required to establish a procedure for the adequate removal of residual quantities from the previous lot and to validate a maximum period of time between two successiv productions in order to avoid problems such as microbial contamination or residue drying for certain forms such as creams or ointments. (September 9, 2003)

Q.7 Clothing: Is it acceptable to have two levels of clothing in the non-sterile manufacturing areas, i.e. one level for operators with full gowning and coveralls and another level for QA auditors and visitors? What environmental monitoring data is required?

A.7 Yes. There are basic clothing requirements for any person entering the manufacturing areas, such as hair, mustache and beard covering, as well as protective garments. However, a firm may decide to apply more stringent requirements for operators, such as dedicated shoes and garments providing a higher level of protection. There are no specific environmental monitoring requirements for clothing worn in the non- sterile manufacturing areas. (September 9, 2003)

Q.8 Can the sampling for the microbial monitoring of air in non-sterile areas where susceptible products are produced be conducted when there are no manufacturing packaging activities?

A.8 The sampling should occur during actual manufacturing or packaging in order to reflect the conditions to which the products being produced are really exposed. Monitoring between production runs is also advisable in order to detect potential problems before they arise. (September 9, 2003)

Q.9 Must written procedures be available to prevent objectionable microorganisms in drug products not required to be sterile?

A.9 Yes. Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, should be established and followed. This means that even though a drug product is not sterile, a firm must follow written procedures that pro-actively prevent contamination and proliferation of microorganisms that are objectionable. (September 9, 2003)

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RAW MATERIAL TESTING - C.02.009 & C.02.010 Updated

Q.1 What are acceptable microbial limits for purified water?

A.1 In accordance with interpretation 3 under Section C.02.009 of the 2002 edition of the GMP Guidelines, specifications for microbial content of purified water should be pharmacopoeial or equivalent. However, firms may set and justify their own microbial limits for purified water (PW) based on at least two factors in production. First is the microbial specification of the finished product or the equipment surfaces which contact the water. The microbial limit for the water as a component should be more stringent than the limit set for the end product. For example, where a finished product has a microbial limit of not more than 100 cfu/ml, the corresponding limit for water as an ingredient in that product should be less than 100 cfu/ml.

The second factor is the validated water system's operational data. Properly controlled and well designed Purified Water systems should be capable of producing validated water quality in the range of 30-50 cfu/ml. Such operational data would not justify establishing a less stringent specification of "not more than 100 cfu/ml." (September 9, 2003)

Q.2 What are requirements of maintaining an impurity profile?

A.2 The USP defines an impurity profile as "a description of the impurities present in a typical lot of drug substance produced by a given manufacturing process." (ref. USP <1086>). Each commercial lot should be comparable in purity to this standard release profile which is developed early on and maintained for each pharmaceutical chemical. We can also call this profile a "Reference Profile" because the quality control unit refers to it (1) when assessing the purity of each batch of active pharmaceutical ingredient (API), and (2) when evaluating the viability of proposed process changes.

For further information regarding the control of impurities, refer to the following documents available on the International Conference on Harmonization Website open link in a new window(http://www.ich.org):

Impurities in New Drug Substances - ICH Topic Q3A(R);
Impurities in New Drug Products - ICH Topic Q3B(R).

(September 9, 2003)

Q.3 Does every individual container of an active pharmaceutical ingredient (API) need to be sampled for identification (ID) purposes regardless of the number of containers of the same lot available or are composite samples acceptable provided they are obtained from a maximum of 10 containers?

A.3 For human drugs, according to interpretation 6.1 under C.02.009, each container of an API must be tested for identity. Therefore, each container must be opened and sampled. Then, 2 options are available:

1) To test every sample for ID using a discriminating method (it is not mandatory to perform all ID tests in the specifications, for example USP, but the test must be specific).

2) The other option is to mix and pool individual samples taken from each containers in a composite sample but without exceeding 10 individual samples in a composite. A specific ID test is then performed on each composite AND, in addition, a potency test is performed to assure the mass balance of the composite. (In such cases, an equal quantity of each individual sample in the composite must be weighed to ensure that the mass balance is representative.)

As an example, say 72 containers of the same lot of an API are received. Each and all containers must be opened and a sample taken from each container. After that, the first option is to test each sample for ID (which implies 72 ID tests). The second option is to combine equal quantities of those individual samples in a way that the number of samples in any composite does not exceed 10 and test those composites for ID and potency. In this case, the easiest way to combine those samples would be 8 composites of 9 individual samples. For a given composite, a potency result of 88.8 % or so would indicate that one of the containers does not contain the right material as each individual sample contributes 1/9 or 11.11% of the total mass of the composite (similarly a result of 77.7 % would indicate 2 containers with the wrong material). In such case, each container selected for this particular composite would have to be tested for ID to pinpoint the one (or more) containers with the wrong material.

However, the use of a composite sample to establish the ID of an API cannot be used when the potency limits are too wide or, similarly, when the precision of the assay method is not sufficient to properly establish the mass balance. (September 9, 2003)

Q.4 Some of our finished products contain active pharmaceutical ingredients (APIs) such as sodium chloride, calcium chloride, magnesium chloride, dextrose...which are generally used as inactive ingredients in pharmaceutical products. This type of API is received in shipments comprising a large number of containers. Is it acceptable to test a reduced number of containers for ID purposes in relation with interpretation 6.1 of Section C.02.009? Updated

A.4 For that type of API, it would be acceptable to perform the ID testing on a reduced number of containers provided that sampling is conducted according to a statistically valid plan. Although (vn+1) is not recognized as a statistically valid plan, it would nevertheless be considered acceptable for the ID testing of such APIs. This approach would only apply in cases where the raw material is sourced directly from the original vendor or from the broker or wholesaler that supplies materials received from the original vendor without changing the existing labels, packaging, certificate of analysis, and general information. The certification program of the raw material vendor is another issue that is covered under the interpretations of C.02.010. (May 12, 2006)

Q.5 An API can be used after the retest date assigned by the API fabricator if a re-analysis done immediately before use shows that it still meets its specifications. Can the new data generated be used by the drug fabricator to assign a longer retest date to future lots of this API obtained from the same fabricator?

A.5 No. The extension of the retest date originally assigned to the API should be supported by data generated through a formal stability protocol. This may require the filing of a notifiable change submission. Please refer to the appropriate review Directorate. (September 9, 2003)

Q.6 What about inactive ingredients?

A.6 Normally, any inactive raw material should bear an expiry date. When an inactive raw material is received without an expiry date, it is not mandatory for the finished product fabricator to assign one if it can be demonstrated based on stability data or other documented evidence that this raw material is not subject to chemical / physical modifications or is not susceptible to microbial contamination. (September 9, 2003)

Q.7 We are a subsidiary of a US corporation. This US corporation supplies us with APIs that are fully tested after receipt on its premises. Can the US site be certified for the purpose of testing exemptions for the Canadian site?

A.7 The US parent company cannot be considered the vendor. To be certified, the vendor must be the original source of the API (the manufacturer - synthetizer). In this instance, the US company would have to certify the manufacturer - synthetizer as per interpretation 1 under C.02.010 and provide this information to the Canadian site. When received by the Canadian site, a specific ID test must be performed and if for an API, the testing must be as per interpretation 6.1 under C.02.009 (i.e. each container sampled and tested). The above mentioned would be acceptable based on the fact that no repackaging is done by the US site, i.e. the materials must be supplied in their original containers with the original labels and Certificate of Analysis © of A) as received from the vendor (manufacturer - synthetizer). (September 9, 2003)

Q.8 (Question regarding interpretation 6 of Section C.02.009 of Annex 3 to the Current Edition of the Good Manufacturing Practices Guidelines for Selected Category IV Monograph Drugs) One would assume that 'sample' in interpretation 6.0 is meant to be understood as the composite sample, comprised of the sub-samples from a statistically significant number of containers of the lot of raw material. Then in interpretation 6.1 respecting identity testing of the active we find the wording "Each sample taken as part of the sampling plan is tested..." What is the requirement? If there are 12 containers of the Active Pharmaceutical Ingredient (API) and we decide that sampling X containers would be sufficient, then would we do one analysis on the composite sample or X number of analyses from X containers?

A.8 For APIs, a statistically valid sampling plan should designate the number of containers to be sampled. Each sample taken from each of the selected containers must be tested for identity. (December 16, 2005)

Q.9 Does Health Canada recommend method transfer/lab qualification as described in USP <1226> methods for drug substances? For excipients?

A.9 Yes. Please refer to interpretation 5 of section C.02.009 of the main GMP Guidelines. Additionally, a similar interpretation is made in the GMP Q&A #10 under Finished Product Testing ( C.02.018 and C.02.019). (December 16, 2005)

Q.10 What documentation does a laboratory have to have in place to be considered qualified to run a test method for raw materials (drug substances and excipients) in order to satisfy Health Canada Regulations?

A.10 As recommended in the proposed USP <1226>, documentation should include a summary of the analytical data, an assessment of the results and comparison to the acceptance criteria, and a conclusion as to the acceptability of the data as they relate to the ability of the laboratory analysts to successfully perform the compendial procedure in the particular laboratory. (December 16, 2005)

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MANUFACTURING CONTROL - C.02.011 & C.02.012

Q.1 Can a single lot number be assigned to two or more co-mingled lots of bulk finished drug products packaged during the same run?

A.1 GMP guidelines require each batch must be identified by an individually numbered manufacturing batch document, each lot or batch of the finished product shall be fully tested against the specification and retained samples for each lot or batch shall be kept. If these requirements are met, a company can decide to package under one lot number from 2 or more manufacturing batches of bulk finished drug products. The shortest expiry date of all the lots packaged must be indicated on the label.

However, in case of a product recall, the company must recall the entire lot comprising all the sub-lots. (September 9, 2003)

Q.2 What is the acceptable deviation in physical counts of finished product stock?

A.2 The allowable deviation between physical counts versus counts as per records (including computer records) should be zero. All finished product stock must be fully accounted for and records of distribution and disposition must be maintained. Any deviations from physical counts versus expected counts as per the records, should be investigated and the results of such investigations should be documented. (September 9, 2003)

Q.3 What is the Inspectorate's position on software verification?

A.3 Software is regarded as an adjunct to procedures, manufacturing controls and records keeping and subject to the GMP Regulations. Software validation is the responsibility of the user.

The Pharmaceutical Inspection Cooperation Scheme (PIC/S) Annex 11: Computerized Systems was adopted by Health Canada in 2003.

Inspectors will review a company's procedures and systems, including computer systems, to determine that the requirements of the GMP Regulations are being met. It is possible that the company will be asked how they know a computer system in place is functioning as it should. (December 16, 2005)

Q.4 When are independent checks by another operator necessary?

A.4 The Guidelines indicate that a number of measures be taken to maintain the integrity of a drug product from the moment the various relevant raw materials enter the plant to the time the finished dosage form is released for sale. These measures seek to eliminate as many sources of error as possible so that only those drugs which have met established specifications are distributed.

One of the approaches proposed to achieve this goal is to have written procedures that ensure that each ingredient added to a batch is subjected to one or more checks for identity and quantity by qualified personnel.

If by its design, construction, operations and security features the procedure is such that the company assures that it is impossible to make an error, an independent check by another operator may not be considered necessary.

Checks for identity and quantity of dispensed materials also require independent checks by a second individual.

However, independent checks that materials have been added to the batch have traditionally been assumed to take place at the time of actual addition of the materials.

Other means of verifying the addition of materials may be considered. One alternative involves checking staged materials in the immediate compounding area prior to starting processing and then afterwards, verifying the empty containers before clearing the compounding area. This would be in conjunction with the use of individual processing rooms, otherwise we would need to be satisfied that there was very good separation of compounding operations. (September 9, 2003)

Q.5 What are the expectations on label accountability?

A.5 It is expected that sufficient controls are in place to ensure that correct labels are applied during a labelling operation and that printed packaging materials are accounted for.

One acceptable means of meeting this requirement is to issue an accurately counted number of labels. That number should be reconciled with the number of labels used, damaged and returned to stock.

In theory, the target set in your procedure should be "0" deviation for labels and other printed packaging materials. However, a certain tolerance can be allowed for a few "not accounted for" labels after reconciliation. The limits should take into account the size of the lot especially if they are set in %, as a 0.1% limit for a 1000 unit lot is quite different than for a 50,000 unit lot. The limits could also depend of the type of labels as some types are easier to manipulate than others. (September 9, 2003)

Q.6 Is verification of empty containers an acceptable check for addition of ingredients?

A.6 Yes. It is acceptable to check staged materials prior to and after processing as a method of checks for addition through verification of empty containers.

The preferred method for conducting addition checks is by direct observation by the verifier. The verification of empty containers is an acceptable alternative, but only where stringent controls exist regarding the handling of dispensed raw materials.

Such controls include:

- assurance that a dispensed raw material does not end up in the wrong batch; locked portable cages are being used by some firms and only pertinent cages are permitted in the room at the same time.
- adequate operator awareness, training and motivation; the operator has to assure that additions are performed in the proper sequence; any spillage of raw materials must be promptly reported.
- pre and post checking should be performed by qualified personnel and whenever possible should be the same person.
- the post processing check must be performed prior to removal of any material from the area.

(September 9, 2003)

Q.7 Are there guidelines for in-house computer systems?

A.7 Computer systems should be validated for their intended purpose and will be reviewed by inspectors to determine that the requirements of the GMP regulations are being met.

The Pharmaceutical Inspection Cooperation Scheme (PIC/S) Annex 11: Computerized Systems was adopted by Health Canada in September 2003 and was implemented in October 2003.

A company is expected to know the efficiency, capability, functionality and reliability of their computer system.

When fully computerized systems are used, backup systems must be available in case of system failure. (December 16, 2005)

Q.8 What are the expectations of software validation pertaining to product release systems?

A.8 Manufacturers are expected to develop and maintain evidence demonstrating that software and equipment are operating as designed. (September 9, 2003)

Q.9 Are quarantine and release stickers required on all containers of raw materials and packaging materials?

A.9 Quarantine and release stickers are required on all containers of raw materials and packaging components to identify status when a physical quarantine/release system is used.

However, such stickers are not required when a validated electronic quarantine system which effectively prevents the possibility of inadvertent use of unreleased material is in place.

When fully computerized storage systems are used, backup systems should be available in case of system failure. (September 9, 2003)

Q.10 Is an answering machine acceptable for recall activation outside normal working hours?

A.10 A telephone answering machine may be used as part of the provisions for off-hours product recall activation. It should provide information on who to contact; their phone numbers etc. Its use, functions and monitoring requirements should be included in the written procedures. (September 9, 2003)

Q.11 Is it necessary to document quantities by lot numbers of finished stock destroyed?

A.11 For products returned to the distributor's facility for destruction due to reasons such as damaged or expired product, it may not be mandatory to document the quantities destroyed by lot number.

For products returned following a recall, it is mandatory to document the returns by lot number as it is a requirement to perform a final reconciliation.

If an establishment recall procedures depend on dates of first and last sale of a given lot, records of destruction by lot numbers may provide necessary information pertaining to accountability per lot. (September 9, 2003)

Q.12 Is there a standard on what should be stated in a recall procedure?

A.12 Regulations C.02.012(1)(a) requires that every fabricator, packager/labeller, distributor, importer, and wholesaler of a drug maintains a system of control that permits complete and rapid recall of any lot of batch of the drug that is on the market. Such a system must be tailored to an individual organization and operation.

A written recall system should be in place to ensure compliance with Section C.01.051 of the Food and Drug Regulations and should include the requirements outlined in interpretations 1.1 to 1.9 under the Manufacturing Control Section C.02.012 of the current GMP Guidelines. (September 9, 2003)

Q.13 Under what circumstances must one initiate a recall?

A.13 The decision to recall a drug product rests with the distributor/importer of the drug.

In most instances, recalls are carried out voluntarily when a company discovers that one or more of its drugs is defective. When a Class 1 or 2 health hazard has been identified, the company is expected to initiate a recall.

In other instances Health Canada may inform a company of findings that one of its drugs is defective and recommends that a recall be initiated. (September 9, 2003)

Q.14 May firms omit second person component weight check if scales are connected to a computer system?

A.14 No, for an automated system that do not include checks on component quality control release status and proper identification of containers.

Yes, for a validated automated system with bar code reader that registers the raw materials identification, lot number and expiry date and that is integrated with the recorded accurate weight data. (September 9, 2003)

Q.15 For a contract fabricator, is it a requirement to test the raw materials offered by customers?

A.15 Testing of raw materials (RM) is a responsibility of the fabricator. Therefore, an observation will be made to a fabricator for not testing a particular RM (even when this RM is provided by the client) if he is not excluded by his client according to a contract. Interpretation 3.2 under Section C.02.012 covers the written agreements with regard to the fabrication, packaging/labelling or testing among the parties involved. If no such agreement is in place, the observation will be made against the party responsible according to the GMP. (September 9, 2003)

Q.16 If the customer asks a contract fabricator not to test a finished product, is it necessary for the contract fabricator to test the product?

A.16 Interpretation 3.2 under Section C.02.012 covers the written agreements with regard to the fabrication, packaging/labelling or testing among the parties involved. If no such agreement is in place, the observation will be made against the party responsible according to the GMP. (September 9, 2003)

Q.17 Is a contract fabricator or packager responsible for qualification of utilities and systems and cleaning validation or is it the responsibility of the distributor? And what about the validation of the manufacturing/packaging process and test methods?

A.17 The contract fabricator is responsible for the qualification of utilities and systems and cleaning validation as those requirements are not product specific.

For process validation and test method validation, the main responsibility rests with the distributor, according to Section C.02.003 of the GMP regulations. The contract fabricator, packager or tester retains responsibility in terms of process or test methods validation unless a written agreement is signed by both parties that excludes the responsibility of the contract fabricator, packager or tester to perform validation activities. (September 9, 2003)

Q.18 How long in advance can the raw materials be weighed?

A.18 It is acceptable to weigh the raw material (RM) a few days prior to the scheduled date of production. However, the firm should be able to demonstrate that the materials and design of the containers in which the RM are weighed and kept will not alter their quality, the characteristics of the RM must also be taken into consideration. Interpretation 2 of Section C.02.026 may provide guidance to this effect. (September 9, 2003)

Q.19 Should virus protection be part of computerised systems (CS) validation?

A.19 Yes. Where a computerised system is exposed to external data-sources, security measures should be part of the system design and maintenance. Where security updates from the vendor, or third-party suppliers are required, their installation should be appropriately evaluated and recorded. (December 16, 2005)

Q.20 Is a written agreement required when an establishment has used an external consultant for computerised systems (CS) validation?

A.20 Yes. Where an external consultant is used to provide a computerized system validation, a formal agreement should be available including a statement of responsibilities, as per the Pharmaceutical Inspection Cooperation Scheme (PIC/S) Annex 11: Computerised Systems adopted by Health Canada in 2003. In general, these agreements are covered in the GMP guidelines under C.02.020 and C.02.012. (December 16, 2005)

Q. 21 (Question regarding interpretation 2 of section C.02.011 of Annex 3 to the Current Edition of the Good Manufacturing Practices Guidelines for Selected Category IV Monograph Drugs) For importers and distributors of Category IV monograph drugs, what is deemed sufficient to meet the requirements to demonstrate that critical production processes have been shown to produce consistent results?

A.21 Importers and distributors of Category IV monograph drugs must have finished product test results that are satisfactory and evidence that each batch was manufactured in accordance with the master production document, for at least 3 batches. (December 16, 2005)

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QUALITY CONTROL DEPARTMENT - C.02.013, C.02.014 & C.02.015

Q.1 If a product fails its particulate matter specifications, can it be released for sale?

A.1 No. The particulate matter requirement is treated in the same way as any other specification: failure would constitute non-compliance with the labelled standard. (September 9, 2003)

Q.2 Are the USP general notices enforceable?

A.2 Yes. The USP General Notices provide in summary form the basic guidelines for interpreting and applying the standards, tests, assays, and other specifications of the USP so that these general statements do not need to be repeated in the various monographs and chapters throughout the book. Where exceptions to the General Notices exist, the wording in an individual monograph or general test chapter takes precedence.

This concept is further emphasized in the introduction to the General Information chapters which states, "The official requirements for Pharmacopeial articles are set forth in the General Notices, the individual monographs, and the General Tests and Assays chapters of this Pharmacopeia." The General Tests and Assays chapters are those numbered lower than 1000. (September 9, 2003)

Q.3 If a lot meets USP specifications but fails the firm's internal specifications, can it be released?

A.3 If a lot does not meet its declared release specifications, then the lot should not be released. Where more stringent internal specifications act as an alert limit and not as the basis for release, then the lot may be released after investigation and justification provided it meets its release specifications. (September 9, 2003)

Q.4 Is it acceptable for firms to export expired drugs for charity?

A.4 No. While it is recognized the dire need for drugs in distressed parts of the world, once the expiration date has passed there is no assurance that the drugs have the safety, identity, strength, quality and purity characteristics they purport or represent to possess. As such, expired drugs are considered adulterated and their introduction or delivery for introduction into commerce is prohibited. (September 9, 2003)

Q.5 Explain the USP measurement uncertainty (MU) requirement for balances.

A.5 USP General Chapter <41> Weights and Balance states a weighing device providing accurate weighing for assay and test is to have MU of less than 0.1% of the reading and gives an example of 50 mg ± 50 µg as acceptable. To qualify MU of a balance, an appropriate NIST traceable weight within the weighing range of the balance is weighed 10 times or more. The resulting weights are calculated so that three times the calculated standard deviation divided by the amount weighed should be less than 0.001.

For different balance class designations and detailed information on weights and balance, the USP General Chapter <41> is to be consulted. (September 9, 2003)

Q.6 Can an older version of an official method be used or must the most updated version always be used?

A.6 In resolving issues of conformance to an "official standard", the most up to date version of the analytical method is the method that must be used to determine compliance. (September 9, 2003)

Q.7 What is the Inspectorate's position on the use of secondary reference standards and what are the conditions for the use of secondary reference standards?

A.7 While the Inspectorate recommends the use of the official standards for the analysis of compendia articles, the use of a secondary RS is acceptable if each lot's suitability is determined prior to use by comparison against the current official reference standard and each lot is requalified periodically in accordance with a written protocol. The protocol should clearly address the receipt, storage, handling and use of primary reference standards, the purification of secondary standards, and their qualification against official reference standards. (September 9, 2003)

Q.8 Is it acceptable to use a third party lab's available pharmacopeial reference standard to qualify an establishment's secondary standard?

A.8 This practice is acceptable providing the contract testing lab has an Establishment Licence (EL) and has been audited by the client to demonstrate its capability to qualify the secondary standard (ie. the official standard and the proper equipment is available on the tester's premises, the method used has been validated, etc.). Transfer of the standard between the sites should be under controlled conditions. (September 9, 2003)

Q.9 What is the Inspectorate's position on the use of loose work sheets as opposed to bound notebooks for the purpose of recording laboratory data?

A.9 The recommended method of recording laboratory data is a bound book but the use of loose work sheets would be acceptable as long as it is controlled by a system or a procedure to ensure that all raw data are true and accurate, properly recorded and captured, adequately maintained and easily retrievable. The system should also provide accountability and traceability of work sheets. (September 9, 2003)

Q.10 It is generally accepted in the industry to perform process validation on three consecutive lots. How does the Inspectorate view validation when reworking is required (i.e. three consecutive incidents will never happen)?

A.10 Reworking of a batch should be a very rare occurrence. As such, validation of reworking is not considered mandatory as it is not generally feasible. The reworking should be carried out in accordance with a defined procedure approved by QC and with the conditions described in interpretation 6 of C.02.014. This procedure should include supplementary measures and testing during the reworking operations to ensure that the quality of the final product is not compromised.

It is mandatory that rework proposals and reworked product also be fully investigated with respect to impact on release characteristics and potential impact on bio-availability. Changes in formulation due to reworks including the incorporation of additional lubricant or dissolution aid or additional critical processes may require comparative bio-availability studies. Furthermore concomitant stability studies must be undertaken on reworked batches to ensure that critical characteristics are not compromised with time due to the rework. (September 9, 2003)

Q.11 Is it mandatory for the approval of a procedure to sign each page or is it acceptable to only sign the first page?

A.11 It is not mandatory for the approvers to sign each page of the procedure. It would also be acceptable to only sign the last page. (September 9, 2003)

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PACKAGING MATERIAL TESTING - C.02.016 & C.02.017

Q.1 What is the Inspectorate's position on 2-mercaptobenzothiazole (MBT) in rubber closures?

A.1 MBT is sometimes used in the manufacture of rubber stoppers used as closures for vials or as components of syringes. Due to the concerns about the potential toxicity of MBT, its use in the manufacture of packaging materials that are in direct contact with injectable drugs is not permitted. (September 9, 2003)

Q.2 Is it necessary to include a chemical identification test in a specification for a packaging component (such as a plastic bottle)? Must this chemical ID be conducted for each lot received? Would vendor certification be considered an acceptable substitution for testing upon receipt?

A.2 If the type of material is described on the Certificate of Analysis © of A) and if a specific test has been performed by the fabricator of the packaging materials confirming the identity of the starting polymer used to manufacture a specific lot, it is not necessary to repeat the chemical ID (such as IR). But each lot of packaging materials should be visually examined to confirm the identity. (September 9, 2003)

Q.3 Can industrial grade nitrogen be used as a blanketing agent during the manufacture of a drug product?

A.3 No. Any gas used as a blanketing agent should be of compendial standard. (September 9, 2003)

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FINISHED PRODUCT TESTING - C.02.018 & C.02.019

Q.1 Do bacteriostasis and fungistasis testing have to be performed for each lot of product in reference to the USP sterility test?

A.1 No. This needs to be established only once for a specific formulation to determine the suitable level of inoculate for that product. If the formulation has not changed for a number of years, periodic verification can be done as microorganisms become resistant to preservatives in a formulation. (September 9, 2003)

Q.2 Does the Inspectorate encourage the use of environmental isolates for preservative effectiveness testing?

A.2 While the use of environmental isolates in addition to the specified compendia cultures is acceptable, the use of environmental isolates alone is not acceptable. (September 9, 2003)

Q.3 What are the Inspectorate's expectations for process parametric release for foreign and Canadian manufacturers?

A.3 The Inspectorate published on its website, in October 2001, the PIC/S document entitled Guidance on Parametric Release. Please note that requests will be considered only for terminally sterilized drugs in their immediate containers and following submission and approval of evidence acceptable according to this guidance. (September 9, 2003)

Q.4 Does the Inspectorate accept ATP bioluminescence technology as an alternate for traditional microbiology; if so, to what extent of validation is required?

A.4 The ATP bioluminescence technology has been studied as an alternate for the traditional standard plate