Good Manufacturing Practices Guidelines, 2002 Edition, Version 2

Contact Information and Complete Document for Printing

Table of Contents:

• Introduction
• Quality Management
• Glossary of Terms
• Regulation
                    C.02.002
                    C.02.003
  • Premises
         C.02.004
  • Equipment
         C.02.005
  • Personnel
         C.02.006
  • Sanitation
         C.02.007
         C.02.008
  • Raw Materiel Testing
         C.02.009
         C.02.010
  • Manufacturing Control
         C.02.011
         C.02.012
  • Quality Control Department
         C.02.013
         C.02.014
         C.02.015
  • Packaging Materiel Testing
         C.02.016
         C.02.017
  • Finished Product Testing
         C.02.018
         C.02.019
  • Records
         C.02.020
         C.02.021
         C.02.022
         C.02.023
         C.02.024
  • Samples
         C.02.025
         C.02.026
  • Stability
         C.02.027
         C.02.028
  • Sterile Products
         C.02.029
  • Medical Gases
         C.02.030

Annex:

• Annex A
  Internationally Harmonized Requirements for Batch Certification
• Annex B
  Alternate Sample Retention Site Application Form
• Annex C
  References
• GMP Committee members

Introduction

These guidelines on Good Manufacturing Practices (GMP) refer to Division 2, Part C of the Food and Drug Regulations. The guidelines apply to pharmaceutical, radiopharmaceutical, biological, and veterinary drugs and were developed by Health Canada in consultation with their stakeholders. These guidelines are designed to facilitate compliance by the regulated industry and to enhance consistency in the application of the regulatory requirements.

Division 1A, Part C of the Food and Drug Regulations defines activities for which GMP compliance is to be demonstrated prior to the issuance of an establishment licence. In addition to these guidelines, further guidance in specific areas is provided in the annexes to this document or in separate documents.

The content of this document should not be regarded as the only interpretation of the GMP Regulations, nor does it intend to cover every conceivable case. Alternative means of complying with these Regulations can be considered with the appropriate scientific justification. Different approaches may be called for as new technologies emerge.

The guidance given in this document has been written with a view to harmonization with GMP standards from other countries and with those of the World Health Organization (WHO), the Pharmaceutical Inspection Cooperation/Scheme (PIC/S) and the International Conference on Harmonization (ICH).

The present edition of this document reflects the results of regulatory revisions due to the implementation of the Mutual Recognition Agreements (MRA) Framework. The MRA establishes mutual recognition of GMP compliance certification and assessment methods by regulatory authorities of countries designated as equivalent.

Acronyms

API: Active Pharmaceutical Ingredient

DIN: Drug Identification Number

GMP: Good Manufacturing Practices

ICH: International Conference on Harmonization

HPFBI: Health Products and Food Branch Inspectorate

NOC: Notice of Compliance

MRA: Mutual Recognition Agreement

PIC/S: Pharmaceutical Inspection Cooperation/Scheme

WHO: World Health Organization

GMP Sections applying to the establishment activity

View GMP Sections applying to the establishment activity Table
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Quality Management

Principle

The holder of an establishment licence, or any operation to which the requirements of Division 2 are applicable, must ensure that the fabrication, packaging, labelling, distribution, testing, and wholesaling of drugs comply with the requirements of the marketing authorization and do not place consumers at risk due to inadequate safety and quality. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment of personnel in many different departments and at all levels within the establishment and its suppliers. To achieve the objective reliably, there must be a comprehensively designed and correctly implemented system of quality assurance that incorporates Good Manufacturing Practices and thus quality control. The system should be fully documented and its effectiveness monitored. All parts of the quality assurance systems should be adequately resourced with qualified personnel, suitable premises, equipment, and facilities. There are additional legislative responsibilities for the holder of the establishment licence and for the person(s) authorized to market drug products.

The basic concepts of quality assurance, Good Manufacturing Practices and quality control are inter-related. They are described here in order to emphasize their relationships and their fundamental importance to the production and control of drugs.

QUALITY ASSURANCE

Quality assurance is a wide-ranging concept that covers all matters that individually or collectively influence the quality of a drug. It is the total of the organized arrangements made with the objective of ensuring that drugs are of the quality required for their intended use. Quality assurance therefore incorporates Good Manufacturing Practices, along with other factors that are outside the scope of these guidelines.

A system of quality assurance appropriate for the manufacture of drugs should ensure that:

1. Drugs are designed and developed in a way that takes into account the GMP requirements;
   
   
2. Managerial responsibilities are clearly specified;
   
   
3. Systems, facilities and procedures are adequate;
   
   
4. Production and control operations are clearly specified, and GMP are adopted;
   
   
5. Arrangements are made for the supply and use of the correct raw and packaging materials;
   
   
6. Control on intermediates, in-process monitoring, and validation activities are carried out;
   
   
7. The finished product is processed, packaged/labelled, verified, and tested according to defined procedures;
   
   
8. Drugs are not sold or supplied before the quality control department has indicated that each batch has been produced and controlled in accordance with the requirements of the marketing authorization and of any other regulations relevant to the production, control and release of drugs;
   
   
9. Satisfactory arrangements exist for ensuring that the drugs are stored, distributed, and subsequently handled in such a way that quality is maintained throughout their shelf life;
   
   
10. There is a procedure for self-inspection and/or quality audit that regularly appraises the effectiveness and applicability of the quality assurance system;

Good Manufacturing Practices (GMP) for Drugs

Good Manufacturing Practices (GMP) are the part of quality assurance that ensures that drugs are consistently produced and controlled in such a way to meet the quality standards appropriate to their intended use, as required by the marketing authorization.

GMP are concerned with both production and quality control. Their basic requirements are as follows:

1. Manufacturing processes are clearly defined and controlled. All critical processes are validated to ensure consistency and compliance with specifications.
   
   
2. Manufacturing processes are controlled, and any changes to the process are evaluated. Changes that have an impact on the quality of the drug are validated as necessary.
   
   
3. All necessary key elements for GMP are provided, including the following:
   
   - qualified and trained personnel
   
   - adequate premises and space
   
   - suitable equipment and services
   
   - correct materials, containers and labels
   
   - approved procedures and instructions
   
   - suitable storage and transport
   
   
4. Instructions and procedures are written in clear and unambiguous language;
   
   
5. Operators are trained to carry out and document procedures;
   
   
6. Records are made, manually or by instruments, during manufacture that demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the drug was as expected. Deviations are investigated and documented;
   
   
7. Records of manufacture (including distribution) that enable the complete history of a batch to be traced are retained in a comprehensible and accessible form;
   
   
8. The distribution of the drugs minimizes any risk to their quality;
   
   
9. A system is available for recalling any batch of drug from sale or supply;
   
   
10. Complaints about marketed drugs are examined, the causes of quality defects are investigated, and appropriate measures are taken with respect to the defective drugs and to prevent recurrence.

Quality Control

Quality control is the part of GMP that is concerned with sampling, specifications, testing, documentation and release procedures. This approach ensures that materials are not released for use, and that drugs released for sale or supply, until their quality has been deemed satisfactory.

The basic requirements of quality control are as follows:

1. Adequate facilities, trained personnel, and approved procedures are available for sampling, inspecting and testing of raw materials, packaging materials, intermediate bulk and finished products, and, where appropriate monitoring environmental conditions for GMP purposes;
   
   1.1 Samples of raw materials, packaging materials, and intermediate, bulk, and finished products are taken according to procedures approved by the quality control department;
   
   1.2 Test methods are validated;
   
   1.3 Records are made that demonstrate that all the required sampling, inspecting, and testing procedures were actually carried out, and any deviations are recorded and investigated;
   
   1.4 The finished products contain active ingredients that comply with the qualitative and quantitative composition requirements of the marketing authorization, have the purity required, are enclosed within their proper container and are correctly labelled;
   
   1.5 Records are made of the results of inspection, and to show that testing of materials, and of intermediate, bulk, and finished products is formally assessed against specification;
   
   1.6 Product assessment includes a review and evaluation of relevant production documentation and an assessment of deviations from specified procedures;
   
   1.7 No batch of drug is released for sale or supply prior to approval by the quality control department, in accordance with the requirements of the marketing authorization (Notice of Compliance (NOC), Drug Identification Number (DIN));
   
   1.8 Sufficient reference samples of raw materials and drugs are retained to permit future examination of the drug if necessary, and the drug is retained in its final pack unless exceptionally large packs are produced.

Glossary of Terms

The definitions given below apply to the terms used in these guidelines, they also apply to the terms used in the annexes unless otherwise specified therein. Definitions quoted from other documents are identified in brackets at the end of the definition.

Active Pharmaceutical Ingredient (ingrédient pharmaceutique actif) - Any substance or mixture of substances that is intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body. (ICH, Q7A, step 5)

Airlock (sas) - An enclosed space with two or more doors, that is interposed between two or more rooms, usually of differing classes of cleanliness, for the purpose of controlling the airflow between those rooms when either people or goods need to enter or leave them.

Aseptic Area (aire aseptique) - A zone or zones within a clean area where Grade A or B (see table in Section C.02.029 of these guidelines) conditions are maintained.

Aseptic Process (procédé aseptique) - A method of producing a sterile product in which sterile bulk drug or sterile raw materials are compounded and assembled with sterile packaging components under Grade A or B conditions (see table in Section C.02.029 of these guidelines).

Batch (lot de fabrication) - A quantity of drug in dosage form, a raw material, or a packaging material, homogeneous within specified limits, produced according to a single production order and as attested by the signatories to the order. In the case of continuous manufacture, a batch corresponds to a defined fraction of the production, that is characterized by its intended homogeneity. It may sometimes be necessary to divide a batch into a number of sub-batches, which are later brought together to form a final homogeneous batch.

Batch Certificate (certificat de lot) - A certificate issued by the fabricator of a lot or batch of a drug that is exported within the framework of a mutual recognition agreement and in which the fabricator

1. identifies the master production document for the drug and certifies that the lot or batch has been fabricated, packaged/labelled and tested in accordance with the procedures described in that document;
   
   
2. provides a detailed description of the drug, including
   
   
   1. a statement of all properties and qualities of the drug, including the identity, potency and purity of the drug, and
      
      
   2. a statement of tolerances for the properties and qualities of the drug;
      
      
3. identifies the analytical methods used in testing the lot or batch and provides details of the analytical results obtained;
   
   
4. sets out the addresses of the buildings at which the lot or batch was fabricated, packaged/labelled and tested; and
   
   
5. certifies that the lot or batch was fabricated, packaged/labelled and tested in accordance with the good manufacturing practices of the regulatory authority that has recognized those buildings as meeting its good manufacturing practices standard. (C.01A.001)
   BATCH NUMBER (numéro de lot de fabrication) - A distinctive combination of numbers and/or letters that specifically identifies a batch. The batch number appears on the batch records, certificates of analysis, etc.

Bracketing (méthode des extrêmes) - The design of a stability schedule such that only samples on the extremes of certain design factors (e.g., strength, package size) are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested. Where a range of strengths is to be tested, bracketing is applicable if the strengths are identical or very closely related in composition (e.g., for a tablet range made with different compression weights of a similar basic granulation, or a capsule range made by filling different plug fill weights of the same basic composition into different sized capsule shells). Bracketing can be applied to different container sizes or to different fills in the same container closure system. (ICH, Q1A(R))

Bulk Drug (drogue en vrac) - Unpackaged dosage form, usually in quantities larger than the largest commercially available package size.

Certificate of Manufacture (certificat de fabrication) - A document issued by a vendor to a distributor or importer that attests that a specific lot or batch of drug has been produced in accordance with its master production document. Such certificates include a detailed summary of current batch documentation, with reference to respective dates of revision, manufacture, and packaging, and are signed and dated by the vendor's quality control department.

Change Control (contrôle des changements) - A written procedure that describes the action to be taken if a change is proposed (a) to facilities, materials, equipment, and/or processes used in the fabrication, packaging, and testing of drugs, or (b) that may affect the operation of the quality or support system.

Changeover Procedure (procédure de conversion) - A logical series of validated steps that ensures the proper cleaning of suites and equipment before the processing of a different product begins.

Clean Area (aire propre) - A room or suite of rooms where Grade C or D conditions (see table in Section C.02.029 of these guidelines) are required. The rooms have a defined environmental control of particulate and microbial contamination and are constructed, maintained, and used in such a way as to minimize the introduction, generation, and retention of contaminants.

Critical Process (procédé critique) - A process that may cause significant variation in the quality of the finished product.

Date of Fabrication (date de fabrication) - Unless otherwise defined in the Food and Drug Regulations, this is the date when any active ingredient, anti-oxidant, preservative, or air/oxygen scavenger is first added to the lot being processed.

Director (directeur) - The Assistant Deputy Minister, Health Products and Food Branch, of the Department of Health. (A.01.010)

Distributor (distributeur) - A person, including an association or partnership, who under their own name, or under a trade, design or word mark, trade name or other name, word, or mark controlled by them, sells a food or drug. (A.01.010)

Divisions 1A and 2 to 4 apply to the following distributors (C.01A.003):

1. a distributor of a drug listed in Schedule C or D to the Act or in Schedule F to these Regulations, a controlled drug as defined in subsection G.01.001 (1) or a narcotic as defined in the Narcotic Control Regulations who does not hold the drug identification number for the drug or narcotic; and
   
   
2. a distributor of a drug for which that distributor holds the drug identification number.

Dosage Form (forme posologique) - A drug product that has been processed to the point where it is now in a form in which it may be administered in individual doses.

Drug (drogue) - Any substance or mixture of substances manufactured, sold, or represented for use in (a) the diagnosis, treatment, mitigation, or prevention of a disease, a disorder, an abnormal physical state, or the symptoms thereof, in humans or animals, (b) restoring, correcting, or modifying organic functions in humans or animals, or ©) "disinfection" in premises in which food is manufactured, prepared, or kept. (Section 2 of the Act)

In Division 1A and Division 2 of the Food and Drug Regulations, "drug" means a drug in dosage form, or a drug that is a bulk process intermediate that can be used in the preparation of a drug listed in Schedule C to the Act or in Schedule D to the Act that is of biological origin. It does not include a dilute drug premix, a medicated feed as defined in Section 2 of the Feeds Regulations, 1983, a drug that is used only for the purposes of an experimental study in accordance with a certificate issued under Section C.08.015 or a drug listed in Schedule H to the Act. (C.01A.001(2))

Fabricate (manufacturer) - To prepare and preserve a drug for the purpose of sale. (C.01A.001)

Fabricator's Batch Certificate (Certificat de fabrication d'un lot) - A certificate delivered under the scope of a mutual recognition agreement for a lot or batch of a drug. (The certificate's content is described in Annex A). Please refer to regulation C.01A.001 (1) for a complete definition of "batch certificate".

Filling (remplissage) - Transferring a bulk drug into its final container and enclosing it in the container.

Finished Product (produit fini) - A product that has undergone all stages of production, including packaging in its final container and labelling.

Formulating (transformation) - Preparing components and combining raw materials into a bulk drug. For sterile products, this includes such steps as cleaning, rinsing, sterilizing, aerating, flushing, and filtering.

Group 2 Products (produits du groupe 2) - Drugs listed in Schedule D to the Act and subject to Health Canada's lot release programme which require the highest level assessment after the notice of compliance (NOC) has been issued. This assessment includes targeted testing, protocol review, and written approval for sale of each lot in Canada in the form of a release letter.

Importer (importateur) - A person who imports into Canada a drug for the purpose of sale.

In-Process Control (contrôle en cours de fabrication) - Checks performed during production in order to monitor and, if necessary, to adjust the process to ensure that the finished product conforms to its specifications. The control of the production environment or equipment may also be regarded as a part of in-process control.

In-Process Drug (drogue semi-finie) - Any material or mixture of materials that must, to become a drug in dosage form, undergo further processing.

In-Process Testing (analyse en cours de fabrication) - The examination or testing of any material or mixture of materials during the manufacturing process.

Installation Qualification (qualification d'installation) - The documented act of demonstrating that process equipment and ancillary systems are appropriately selected and correctly installed.

Label (étiquette) - Any legend, word, or mark attached to, included in, belonging to, or accompanying any food, drug, cosmetic, device, or package. (Section 2 of the Act)

Long Term Testing (analyses à long terme) - Stability studies under the recommended storage condition, for the re-test period or shelf life proposed (or approved) for labelling. (ICH, Q1A(R))

Lot (lot) - A quantity of any drug in dosage form, a raw material, or a packaging material, homogeneous within specified limits, constituting all or part of a single batch and identified by a distinctive lot number that appears on the label of the finished product.

Lot Failure (lot défectueux) - A lot or batch that has been rejected due to failure to meet in process or final product release specifications.

Lot Number (numéro de lot) - Any combination of letters, figures, or both, by which any food or drug can be traced in manufacture and identified in distribution. (A.01.010)

Manufacturing Batch Document (fiche de lot de fabrication) - Instructions that outline in detail the materials and procedures required to fabricate, prepare, and preserve a single lot or batch of a drug in dosage form.

Marketing Authorization (autorisation de mise en marché) - A legal document issued by Health Canada, authorizing the sale of a drug product in Canada; it includes a Notice of Compliance (NOC) or a Drug Identification Number (DIN).

Mass Balance (somme des masses) - The process of adding together the assay value and levels of degradation products to see how closely these add up to 100% of the initial value, with due consideration of the margin of analytical error. (ICH, Q1A(R))

Master Formula (formule-type) - A document or set of documents specifying the raw materials with their quantities and the packaging materials, together with a detailed description of the procedures and precautions required to produce a specified quantity of a finished product as well as the processing instructions, including the in-process controls.

Master Production Document (document-type de production) - a document that includes specifications for raw material, for packaging material and for packaged dosage form, master formula, sampling procedures, and critical processing related SOPs, whether or not these SOPs are specifically referenced in the master formula.

Matrixing (méthode de la matrice) - The design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations is tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations is tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point. The differences in the samples for the same drug product should be identified as, for example, covering different batches, different strengths, different sizes of the same container closure system, and possibly in some cases, different container closure systems. (ICH, Q1A(R))

MRA Country (pays participant) - A country that is a participant in a mutual recognition agreement with Canada.(C.01A.001)

Mutual Recognition Agreement (accord de reconnaissance mutuelle) - An international agreement that provides for the mutual recognition of compliance certification for Good Manufacturing Practices for drugs. (C.01A.001)

Operational Qualification (qualification opérationelle) - The documented action of demonstrating that process equipment and ancillary systems work correctly and operate consistently in accordance with established specifications.

Package/Label (emballer/étiqueter) - To put a drug in its immediate container or to affix the inner or outer label to the drug. (C.01A.001)

Packaging (emballage) - Operations required to package and label a single lot or batch of a drug in dosage form.

Packaging Material (matériel d'emballage) - Labels, printed packaging materials and those components in direct contact with the dosage form. (refer to C.02.002)

Packaging Batch Document (fiche d'emballage de lot de fabrication) - Instructions that outline in detail the materials and special procedures required to package and label a single lot or batch of a drug in dosage form.

Parenteral Use (usage parentéral) - Administration of a drug by means of hypodermic syringe, needle or other instrument through or into the skin or mucous membrane. (C.01.001)

Pharmaceutical (produit pharmaceutique) - A drug other than a drug listed in Schedule C or D to the Act. (C.01A.001)

Potency (teneur) - The activity or amount of active moiety, or any form thereof, indicated by l abel claim to be present.

Process Qualification (qualification de procédé) - The phase of validation dealing with sampling and testing at various stages of the manufacturing process to ensure that product specifications are met.

Production (production) - All operations involved in the preparation of a finished product, from receipt of materials, through processing and packaging, to completion of the finished product, including storage.

Purified Water (eau purifiée) - As defined in any standard listed in Schedule B to the Food and Drugs Act.

Purity (pureté) - The extent to which a raw material or a drug in dosage form is free from undesirable or adulterating chemical, biological, or physical entities as defined by specification.

Qualified Personnel (personnel qualifié) - Individuals who have the appropriate education, training and experience to perform their duties.

Qualified Authority (autorité qualifiée) - An authority member of the Pharmaceutical Inspection Cooperation/Scheme (PIC/S) or the United States Food and Drug Administration (USFDA).

Quality Control Department (service du contrôle de la qualité) - A separate and distinct operation, maintained by a manufacturer or an importer, that is responsible only to management, and that monitors the quality of production operations and exercises control over the quality of materials required for and resulting from those operations.

Quarantine (quarantaine) - Effective restriction of the availability of material or product for use (physically or by system), until released by the quality control department.

Raw Material (matière première) - Any substance, other than in-process drug or packaging material, intended to be used in the manufacture of drugs, including those that appear in the master formula but that do not appear in the drug such as solvents and processing aids.

Recognized Building (bâtiment reconnu) - In respect of the fabrication, packaging/labelling or testing of a drug, a building that a regulatory authority that is designated under subsection C.01A.019(1) in respect of that activity has recognized as meeting its Good Manufacturing Practices standards in respect of that activity for that drug.(C.01A.001)

Reconciliation (bilan comparatif) - A comparison, making due allowance for normal variation, between the amount of product or materials theoretically produced or used and the amount actually produced or used.

Recovery (récupération) - The introduction of all or part of previous batches of the required quality into another batch at a defined stage of manufacture.

Regulatory Authority (autorité réglementaire) - A government agency or other entity in an MRA country that has a legal right to control the use or sale of drugs within that country and that may take enforcement action to ensure that drugs marketed within its jurisdiction comply with legal requirements.

Reprocessing (retraitement) - Subjecting all or part of a batch or lot of an in-process drug, a bulk process intermediate (final biological bulk intermediate) or a bulk drug of a single batch/lot to a previous step in the validated manufacturing process due to failure to meet predetermined specifications. Reprocessing procedures are foreseen as occasionally necessary and are validated and pre-approved by the quality control department or as part of the marketing authorization.

Re-Test Date (date de ré-analyse) - The date when samples of a drug substance are re-examined to ensure that the material is still suitable for use.

Re-Test Period (période de ré-analyse) - The period of time during which a drug substance can be considered to remain within the specifications and therefore acceptable for use in the fabrication of a given drug product, provided that it has been stored under defined conditions; after this period, the batch is re-tested for compliance with specifications and then used immediately. (ICH, Q1A(R))

Returned Product (produit retourné) - Bulk drug or finished product sent back to the manufacturer or importer.

Reworking (reprise) - Subjecting an in-process drug, a bulk process intermediate (final biological bulk intermediate), or final product of a single batch/lot to an alternate manufacturing process due to a failure to meet predetermined specifications. Reworking is an unexpected occurrence and is not pre-approved as part of the marketing authorization. (WHO GMP)

Self-Contained Facility - (installation confinée) - means premises that provide complete and total separation of all aspects of the operation, including personnel and equipment movement, with well established procedures, controls and monitoring. This includes physical barriers as well as separate air handling systems. Self-contained facilities does not necessarily imply two distinct and separate buildings.

Sell (vendre) - Offer for sale, expose for sale, have in possession for sale, and distribute, regardless of whether the distribution is made for consideration. (Section 2 of the Act)

Shelf Life / Expiration Dating Period - (durée de conservation/période de péremption) - The time interval during which a drug product is expected to remain within the approved specification provided that it is stored under the conditions defined on the label and in the proposed containers and closure.

Standard Operating Procedure (SOP) - (procédure opératoire normalisée) - A written procedure giving instructions for performing operations not necessarily specific to a given product or material but of a more general nature (e.g., equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control; sampling and inspection). Certain SOPs may be used to supplement product-specific master and batch production documents.

Sterile (stérile) - Free from viable microorganisms.

System (système) - A regulated pattern of interacting activities and techniques that are united to form an organized whole.

Terminal Sterilization (stérilisation en phase terminale) - Sterilizing a drug in its final closed container.

Validation (validation) - The documented act of demonstrating that any procedure, process, and activity will consistently lead to the expected results. Includes the qualification of systems and equipment.

Vendor (vendeur) - The fabricator of the item.

Wholesale (vendre en gros) - To sell any of the following drugs, other than at retail sale, where the seller's name does not appear on the label of the drugs:

1. a drug listed in Schedule C or D to the Act or in Schedule F to these Regulations or a controlled drug as defined in subsection G.01.001 (1); or
   
   
2. a narcotic as defined in the Narcotic Control Regulations. (C.01A.001)

Regulation

C.02.002

In this Division,

• "medical gas" means any gas or mixture of gases manufactured, sold, or represented for use as a drug; (gaz médical)
  
  
• "packaging material" includes a label; (matériel d'emballage)
  
  
• "quality control department" means a quality control department referred to in section C.02.013; (service du contrôle de la qualité)
  
  
• "specifications" means a detailed description of a drug, the raw material used in a drug, or the packaging material for a drug and includes:
  
  
  1. a statement of all properties and qualities of the drug, raw material or packaging material that are relevant to the manufacture, packaging, and use of the drug, including the identity, potency, and purity of the drug, raw material, or packaging material,
     
     
  2. a detailed description of the methods used for testing and examining the drug, raw material, or packaging material, and
     
     
  3. a statement of tolerances for the properties and qualities of the drug, raw material, or packaging material. (spécifications)

Sale

C.02.003

No distributor referred to in paragraph C.01A.003(b) and no importer shall sell a drug unless it has been fabricated, packaged/labelled, tested, and stored in accordance with the requirements of this Division.

Premises

Regulation

C.02.004

The premises in which a lot or batch of a drug is fabricated or packaged/labelled shall be designed, constructed and maintained in a manner that;

1. permits the operations therein to be performed under clean, sanitary and orderly conditions;
   
   
2. permits the effective cleaning of all surfaces therein; and
   
   
3. prevents the contamination of the drug and the addition of extraneous material to the drug.

Rationale

The pharmaceutical establishment should be designed and constructed in a manner such that it permits cleanliness and orderliness while preventing contamination. Regular maintenance is required to prevent deterioration of the premises. The ultimate objective of all endeavours is product quality.

Interpretation

1. Buildings are located in an environment that, when considered together with measures being taken to protect the manufacturing processes, presents a minimum risk of causing any contamination of materials or drugs.
   
   
2. The premises are designed, constructed, and maintained such that they prevent the entry of insects and other animals into the building and also prevent the migration of extraneous material from the outside into the building and from one area to another.
   
   2.1 Doors, windows, walls, ceilings, and floors are such that no holes or cracks are evident (other than those intended by design).
   
   2.2 Doors giving direct access to the exterior from manufacturing and packaging areas are used for emergency purposes only. These doors are adequately sealed. Receiving and shipping area(s) do not allow direct access to production areas.
   
   2.3 Production areas are segregated from all non-production areas. Individual manufacturing, packaging, and testing areas are clearly defined and if necessary segregated. Areas where biological, microbiological or radioisotope testing is carried out require special design and containment considerations.
   
   2.4 Laboratory animals' quarters are segregated.
   
   2.5 Engineering, boiler rooms, generators, etc. are isolated from production areas.
   
   
3. In all areas where raw materials, in-process drugs, or drugs are exposed, the following considerations apply to the extent necessary to prevent contamination. In laboratories these considerations apply only to the extent necessary to ensure the validity of test results.
   
   3.1 Floors, walls, and ceilings permit cleaning. Brick, cement blocks, and other porous materials are sealed. Surface materials that shed particles are avoided.
   
   3.2 Floors, walls, ceilings, and other surfaces are hard, smooth and free of sharp corners where extraneous material can collect.
   
   3.3 Joints between walls, ceilings and floors are sealed.
   
   3.4 Pipes, light fittings, ventilation points and other services do not create surfaces that cannot be cleaned.
   
   3.5 Floor drains are screened and trapped.
   
   3.6 Air quality is maintained through dust control, monitoring of pressure differentials between production areas and periodic verification and replacement of air filters. The air handling system is well defined, taking into consideration airflow volume, direction, and velocity. Air handling systems are subject to periodic verification to ensure compliance with their design specifications. Records are kept.
   
   
4. Temperature and humidity are controlled, where required, in order to safeguard sensitive materials (e.g. raw materials, drugs, samples, reference standards, etc.).
   
   
5. Rest, change, wash-up, and toilet facilities are well separated from production areas and are sufficiently spacious, well ventilated, and of a type that permits good sanitary practices.
   
   
6. Premises layout is designed to avoid mix-ups and generally optimize the flow of personnel and materials.
   
   6.1 There is sufficient space for receiving and all production activities.
   
   6.2 Working spaces allow the orderly and logical placement of equipment (including parts and tools) and materials.
   
   6.3 Where physical quarantine areas are used, they are well marked, with access restricted to designated personnel. Where electronic quarantine is used, electronic access is restricted to designated personnel.
   
   6.4 A separate sampling area is provided for raw materials. If sampling is performed in the storage area, it is conducted in such a way as to prevent contamination or cross-contamination.
   
   6.5 Working areas are well lit.
   
   
7. Utilities and support systems (e.g., HVAC, dust collection, and supplies of purified water, steam, compressed air, nitrogen, etc.) are qualified and are subject to periodic verification.
   
   
8. Outlets for liquids and gases used in the production of drugs are clearly identified as to their content.
   
   
9. Premises are maintained in a good state of repair. Repair and maintenance operations do not affect drug quality.
   
   
10. Where necessary, separate rooms are provided and maintained to protect analytical instruments and associated control systems from vibration, electrical interference, and contact with excessive moisture or other external factors.
    
    
11. Prevention of cross-contamination during manufacturing is the responsibility of the fabricator and packager. They must demonstrate that the premises are designed in such a manner that the risk of cross-contamination between products is minimized.
    
    11.1 In order to minimize the risk of a serious health hazard due to cross-contamination, additional controls, including the need for self-containment should be considered for particular drugs, such as the following:
    
    - highly sensitizing drugs (e. g., penicillins)
    
    - biologicals (e. g., live vaccines)
    
    - certain hormones (e. g., estrogen)
    
    - certain cytotoxic drugs
    
    - other highly active drugs
    
    Factors to consider are the manufacturing processes, the use of closed systems, dedication of product contact equipment parts, HVAC controls, and engineering controls (such as fail-safe systems), coupled with validation and ongoing monitoring using highly sensitive analytical methods.
    
    11.2 Campaign production can be accepted where, on a product by product basis, proper justification is provided, validation is conducted and rigorous validated controls and monitoring are in place and demonstrate the minimization of any risk of cross- contamination.
    
    11.3 No production activities of highly toxic non-pharmaceutical materials, such as pesticides and herbicides, are conducted in premises used for the production of drugs.
    
    11.4 Once the products are enclosed in their immediate final containers, co- mingle storage in warehouses is allowed.
    
    Self-contained facility means premises that provide complete and total separation of all aspects of the operation, including personnel and equipment movement, with well established procedures, controls and monitoring. This includes physical barriers as well as separate air handling systems. Self-contained facilities does not necessarily imply two distinct and separate buildings.

Equipment

Regulation

C.02.005

The equipment with which a lot or batch of a drug is fabricated, packaged/labelled, or tested shall be designed, constructed, maintained, operated, and arranged in a manner that:

1. permits the effective cleaning of its surfaces;
   
   
2. prevents the contamination of the drug and the addition of extraneous material to the drug; and
   
   
3. permits it to function in accordance with its intended use.

Rationale

The purpose of these requirements is to prevent the contamination of drugs by other drugs, by dust, and by foreign materials such as rust, lubricant and particles coming from the equipment. Contamination problems may arise from poor maintenance, the misuse of equipment, exceeding the capacity of the equipment and the use of worn-out equipment. Equipment arranged in an orderly manner permits cleaning of adjacent areas and does not interfere with other processing operations. It also minimizes the circulation of personnel and optimizes the flow of materials. The fabrication of drugs of consistent quality requires that equipment perform in accordance with its intended use.

Interpretation

1. The design, construction and location of equipment permit cleaning, sanitizing, and inspection of the equipment.
   
   1.1 Equipment parts that come in contact with raw materials, in-process drugs or drugs are accessible to cleaning or are removable.
   
   1.2 Tanks used in processing liquids and ointments are equipped with fittings that can be dismantled and cleaned. Validated Clean-In-Place (CIP) equipment can be dismantled for periodic verification.
   
   1.3 Filter assemblies are designed for easy dismantling.
   
   1.4 Equipment is located at a sufficient distance from other equipment and walls to permit cleaning of the equipment and adjacent area.
   
   1.5 The base of immovable equipment is adequately sealed along points of contact with the floor.
   
   1.6 Equipment is kept clean, dry and protected from contamination when stored.
   
   
2. Equipment does not add extraneous material to the drug.
   
   2.1 Surfaces that come in contact with raw materials, in-process drugs or drugs are smooth and are made of material that is non-toxic, corrosion resistant, non-reactive to the drug being fabricated or packaged and capable of withstanding repeated cleaning or sanitizing.
   
   2.2 The design is such that the possibility of a lubricant or other maintenance material contaminating the drug is minimized.
   
   2.3 Equipment made of material that is prone to shed particles or to harbour microorganisms does not come in contact with or contaminate raw materials, in-process drugs or drugs.
   
   2.4 Chain drives and transmission gears are enclosed or properly covered.
   
   2.5 Tanks, hoppers and other similar fabricating equipment are equipped with covers.
   
   
3. Equipment is operated in a manner that prevents contamination.
   
   3.1 Ovens, autoclaves and similar equipment contain only one raw material, in-process drug or drug at a time, unless precautions are taken to prevent contamination and mix-ups.
   
   3.2 Equipment is not operated where contaminants may fall into the material.
   
   3.3 Equipment is placed in such a way to optimize the flow of material and to minimize the circulation of personnel.
   
   3.4 Equipment is located so that production operations undertaken in a common area are compatible and so that prevent cross contamination between such operations is prevented.
   
   3.5 Fixed pipework is clearly labelled to indicate the contents and, where applicable, the direction of flow.
   
   3.6 Dedicated production equipment is provided where appropriate.
   
   3.7 Water purification, storage, and distribution equipment is operated in such a manner so as to ensure a reliable source of water of the appropriate chemical and microbial purity.
   
   
4. Equipment is maintained in a good state of repair when in use.
   
   4.1 Where a potential for the contamination of the drug being fabricated or packaged exists, surfaces are free from cracks, peeling paint and other defects.
   
   4.2 Gaskets are functional.
   
   4.3 The use of temporary devices such as tape is avoided.
   
   4.4 Equipment parts that come in contact with drugs are maintained in such a manner that drugs are fabricated or packaged within specifications.
   
   
5. Production equipment is designed, located, and maintained to serve its intended purpose.
   
   5.1 Scales and other measuring equipment of an appropriate range and precision are available for production and control operations. Such equipment is calibrated on a scheduled basis, and corresponding records are kept.
   
   5.2 Defective and unused equipment is removed from production and quality control areas or is at least clearly labelled as such.
   
   5.3 Equipment intended to be used during the critical steps of fabrication, packaging/labelling, and testing is subject to installation and operational qualification. Equipment qualification is documented.
   
   5.4 Automatic, mechanical, electronic, or other types of equipment including computerized systems that are used in the fabrication, packaging/labelling, and storing of a drug is routinely calibrated, inspected or checked according to a written program designed to assure proper performance. Written records of these calibration checks and inspections are maintained.
   
   5.5 Equipment usage logs are maintained.

Personnel

Regulation

C.02.006

Every lot or batch of a drug shall be fabricated, packaged/labelled, tested, and stored under the supervision of personnel who, having regard to the duties and responsibilities involved have had such technical, academic, and other training as the Director considers satisfactory in the interests of the health of the consumer or purchaser.

Rationale

People are the most important element in any pharmaceutical operation, without the proper personnel with the right attitude and the right training, it is almost impossible to fabricate, package/label, test, or store good quality drugs.

It is essential that qualified personnel be employed to supervise the fabrication of drugs. The operations involved in the fabrication of drugs are highly technical in nature and require constant vigilance, attention to details and a high degree of competence on the part of employees. Inadequate training of personnel or the absence of an appreciation of the importance of production control, often accounts for the failure of a product to meet the required standards.

Interpretation

1. For fabricators, packagers/labellers and testers, individuals in charge of the manufacturing department and the quality control department;
   
   1.1 hold a university degree or equivalent in a science related to the work being carried out;
   
   1.2 have practical experience in their responsibility area;
   
   1.3 directly control and personally supervise on site, activities under their control; and
   
   1.4 can delegate their duties and responsibility 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, while remaining accountable for those duties and responsibility.
   
   
2. Individuals responsible for packaging operations, including control over printed packaging materials and withdrawal of bulk drugs;
   
   2.1 are qualified by training and experience; and
   
   2.2 are directly responsible to the person in charge of the manufacturing department or a person having the same qualifications.
   
   
3. For distributors, importers, and wholesalers, individuals in charge of the quality control department;
   
   3.1 are qualified by pertinent academic training and experience; and
   
   3.2 can delegate their duties and responsibilities to a person who meets the requirements defined under Regulation C.02.006 Interpretation 3.1.
   
   
4. An adequate number of personnel with the necessary qualifications and practical experience appropriate to their responsibilities are available on site.
   
   4.1 The responsibilities placed on any one individual are not so extensive as to present any risk to quality.
   
   4.2 All responsible personnel have their specific duties recorded in a written description and have adequate authority to carry out their responsibilities.
   
   4.3 When key personnel are absent, qualified personnel are appointed to carry out their duties and functions.
   
   
5. All personnel are aware of the principles of GMP that affect them, and all personnel receive initial and continuing training relevant to their job responsibilities.
   
   5.1 Training is provided by qualified personnel having regard to the function and in accordance with a written program for all personnel involved in the fabrication of a drug, including technical, maintenance, and cleaning personnel.
   
   5.2 The effectiveness of continuing training is periodically assessed.
   
   5.3 Training is provided prior to implementation of new or revised SOPs.
   
   5.4 Records of training are maintained.
   
   5.5 Personnel working in areas where highly active, toxic, infectious, or sensitizing materials are handled are given specific training.
   
   5.6 The performance of all personnel is periodically reviewed.
   
   
6. Consultants and contractors have the necessary qualifications, training, and experience to advise on the subjects for which they are retained.

Sanitation

Regulation

C.02.007

1. Every person who fabricates or packages/labels a drug shall have a written sanitation program that shall be implemented under the supervision of qualified personnel.
   
   
2. The sanitation program referred to in subsection (1) shall include:
   
   
   1. cleaning procedures for the premises where the drug is fabricated or packaged/labelled and for the equipment used in the fabrication or packaging/labelling of the drug; and
      
      
   2. instructions on the sanitary fabrication and packaging/labelling of drugs and the handling of materials used in the fabrication and packaging/labelling of drugs.

Rationale

Sanitation in a pharmaceutical plant influences the quality of drug products as well as employee attitude. The quality requirement for drug products demand that such products be fabricated and packaged in areas that are free from environmental contamination and free from contamination by another drug.

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

Interpretation

1. A written sanitation program is available on the premises of every person who fabricates, packages/labels, a drug.
   
   
2. The sanitation program contains procedures that outline the following:
   
   2.1 cleaning requirements applicable to all production areas of the plant with emphasis on manufacturing areas that require special attention;
   
   2.2 cleaning requirements applicable to processing equipment;
   
   2.3 cleaning intervals;
   
   2.4 products for cleaning and disinfection, along with their dilution and the equipment to be used;
   
   2.5 the responsibilities of any outside contractor;
   
   2.6 disposal procedures for waste material and debris;
   
   2.7 pest control measures;
   
   2.8 precautions required to prevent contamination of a drug when rodenticides, insecticides, and fumigation agents are used;
   
   2.9 microbial and environmental monitoring procedures with alert and action limits in areas where susceptible products are fabricated or packaged; and
   
   2.10 the personnel responsible for carrying out cleaning procedures.
   
   
3. The sanitation program is implemented and is effective in preventing unsanitary conditions.
   
   3.1 Cleaning procedures for manufacturing equipment are validated based on the Cleaning Validation Guidelines.
   
   3.2 Residues from the cleaning process itself (e.g., detergents, solvents, etc.) are also removed from equipment;
   
   3.3 Evidence is available demonstrating that routine cleaning and storage does not allow microbial proliferation;
   
   3.4 Analytical methods used to detect residues or contaminants are validated.
   
   3.5 A cleaning procedure requiring complete product removal may not be necessary between batches of the same drug.
   
   
4. Individuals who supervise the implementation of the sanitation program;
   
   4.1 are qualified by training or experience; and
   
   4.2 are directly responsible to a person who has the qualifications described under Regulation C.02.006.
   
   
5. Dusty operations are contained. The use of unit or portable dust collectors is avoided in fabrication areas especially in dispensing, unless the effectiveness of their exhaust filtration is demonstrated and the units are regularly maintained in accordance with written approved procedures.

Regulation

C.02.008

1. Every person who fabricates or packages/labels a drug shall have in writing, minimum requirements for the health and the hygienic behaviour and clothing of personnel to ensure the clean and sanitary fabrication and packaging/labelling of the drug.
   
   
2. No person shall have access to any area where a drug is exposed during its fabrication or packaging/labelling if the person
   
   
   1. is affected with or is a carrier of a disease in a communicable form, or
      
      
   2. has an open lesion on any exposed surface of the body

Rationale

Employee's health, behaviour, and clothing may contribute to the contamination of the product. Poor personal hygiene will nullify the best sanitation program and greatly increase the risk of product contamination.

Interpretation

1. Minimum health requirements are available in writing and provide for the following:
   
   1.1 Personnel who have access to any area where a drug is exposed during its fabrication or packaging/labelling must undergo health examinations prior to employment. Medical re-examinations, based on job requirements take place periodically.
   
   1.2 Periodic eye examinations are required for personnel who conduct visual inspections.
   
   1.3 When an employee has been absent from the workplace due to an illness that may adversely affect the quality of products, that employee's health is assessed before he or she is allowed to return to the workplace.
   
   1.4 Actions to be taken in the event of a positive diagnosis or a case suspected of being hazardous to consumers of the products are specified.
   
   1.5 Supervisory checks are conducted to prevent any person who has an apparent illness or open lesions that may adversely affect the quality of drugs from handling exposed raw materials, packaging materials, in-process drugs or finished products until the condition is no longer judged to be a risk.
   
   1.6 Employees are instructed to report to their supervisor any health conditions they have that could adversely affect drug products.
   
   
2. The hygiene program clearly defines clothing requirements and hygiene procedures for personnel and visitors.
   
   2.1 Where a potential for the contamination of a raw material, in-process material or drug exists, individuals wear clean clothing and protective covering.
   
   2.2 Direct skin contact is avoided between the operator's hands and raw materials, primary packaging materials and intermediate or bulk drug.
   
   2.3 Unsanitary practices such as smoking, eating, drinking, chewing, and keeping plants, food, drink, smoking material and personal medicines are not permitted in fabrication, packaging/labelling, and storage areas or in any other areas where they might adversely influence product quality.
   
   2.4 Requirements concerning personal hygiene, with an emphasis on hand hygiene, are outlined and are followed by employees.
   
   2.5 Requirements concerning cosmetics and jewelry worn by employees are outlined and are observed by employees.
   
   2.6 Soiled protective garments, if reusable, are stored in separate containers until properly laundered and, if necessary, disinfected or sterilized.
   
   2.7 Personal hygiene procedures including the use of protective clothing, apply to all persons entering production areas.

Raw Material Testing

Regulation

C.02.009

1. Each lot or batch of raw material shall be tested against the specifications for the raw material prior to its use in the production of a drug.
   
   
2. No lot or batch of raw material shall be used in the production of a drug unless that lot or batch of raw material complies with the specifications for that raw material.
   
   
3. Notwithstanding subsection (1), water may, prior to the completion of its tests under that subsection, be used in the production of a drug.
   
   
4. Where any property of a raw material is subject to change on storage, no lot or batch of that raw material shall be used in the production of a drug after its storage unless the raw material is retested after an appropriate interval and complies with its specifications for that property.
   
   
5. Where the specifications referred to in subsections (1), (2) and (4) are not prescribed, they shall
   
   
   1. be in writing;
      
      
   2. be acceptable to the Director, who shall take into account the specifications contained in any publication mentioned in Schedule B to the Act; and
      
      
   3. be approved by the person in charge of the quality control department.

Rationale

The testing of raw materials before their use has three objectives: to confirm the identity of the raw materials, to provide assurance that the quality of the drug in dosage form will not be altered by raw material defects, and to obtain assurance that the raw materials have the characteristics that will provide the desired quantity or yield in a given manufacturing process.

Interpretation

1. Each raw material used in the production of a drug is covered by specifications (see regulation C.02.002) that are approved and dated by the person in charge of the quality control department or by a designated alternate who meets the requirements described under Regulation C.02.006, Interpretation 1.4.
   
   
2. Specifications are of pharmacopoeial or equivalent status and are in compliance with the current marketing authorization. Where appropriate, additional properties or qualities not addressed by the pharmacopoeia (e.g., particle size, etc.) are included in the specifications.
   
   
3. Where a recognized pharmacopoeia (Schedule B of the Food and Drugs Act) contains a specification for microbial content, that requirement is included.
   
   
4. Purified water that meets any standard listed in Schedule B of the Food and Drugs Act is used in the formulation of a drug product, unless otherwise required in one of these standards or as stated in the marketing authorization.
   
   
5. Test methods are validated, and the results of such validation studies are documented. Full validation is not required for methods included in any standard listed in Schedule B to the Food and Drugs Act, but the user of such a method establishes its suitability under actual conditions of use.
   
   Note: Guidance for the validation of particular types of methods can be obtained in publications such as the International Conference on Harmonization (ICH) guidelines titled "Validation of Analytical Procedures: Methodology" or in any standard listed in Schedule B to the Food and Drugs Act.
   
   
6. A sample of each lot of raw material is fully tested against specifications. Sampling is conducted according to a statistically valid plan.
   
   6.1 In addition, each container of a lot of an active pharmaceutical ingredient (API) is tested for the identity of its contents using a specifically discriminating identity test.
   
   In lieu of testing each container for identity, testing a composite sample is acceptable, as long as the following conditions are met:
   
        6.1.1 the number of individual containers for each composite
        sample does not exceed 10; and
   
        6.1.2 a potency test is performed on each composite sample
        to establish the mass balance of the composite sample.
   
   6.2 APIs originating from a dedicated facility that fabricates only one ingredient are exempted from the requirements outlined under Interpretation 6.1, provided that no re-packaging or re-labelling has taken place.
   
   
7. Only raw materials that have been released by the quality control department and that are not past their established re-test date are used in fabrication.
   
   
8. If any API is held in storage after the established re-test date, that API is quarantined, evaluated, and tested prior to use. The re-test date is based on acceptable stability data developed under predefined conditions or on any other acceptable evidence. A batch of raw material can be re-tested and used immediately (i.e., within 30 days) after the re-test as long as it continues to comply with the specifications.
   
   
9. Any inactive raw material that is subject to chemical, microbiological, or physical changes is quarantined, evaluated and tested prior to use if the material has passed the expiration date as determined by the stability data or by any other documented evidence.
   
   
10. For most biotechnological/biological substances and certain antibiotics known to be labile, a shelf life is established rather than a re-test date.

Regulation

C.02.010

1. The testing referred to in section C.02.009 shall be performed on a sample taken
   
   
   1. after receipt of each lot or batch of raw material on the premises of the fabricator; or
      
      
   2. subject to subsection (2), before receipt of each lot or batch of raw material on the premises of the fabricator, if
      
      
      1. the fabricator
         
         
         1. has evidence satisfactory to the Director to demonstrate that raw materials sold to him by the vendor of that lot or batch of raw material are consistently manufactured in accordance with and consistently comply with the specifications for those raw materials, and
            
            
         2. undertakes periodic complete confirmatory testing with a frequency satisfactory to the Director and
            
            
      2. the raw material has not been transported or stored under conditions that may affect its compliance with the specifications for that raw material.
         
         
2. After a lot or batch of raw material is received on the premises of the fabricator, the lot or batch of raw material shall be tested for identity.

Rationale

Section C.02.010 outlines options as to when the testing prescribed by Section C.02.009 is carried out. The purchase of raw materials is an important operation that requires a particular and thorough knowledge of the raw materials and their fabricator. To maintain consistency in the fabrication of drug products, raw materials should originate from reliable fabricators.

Interpretation

1. Testing other than identity testing:
   
   The testing is performed on a sample taken after receipt of the raw material on the premises of the person who formulates the raw material into dosage form, unless the vendor is certified. A raw material vendor certification program, if employed, is documented in a standard operating procedure. At a minimum, such a program includes the following:
   
   1.1 A written contract outlining the specific responsibilities of each party involved. The contract specifies:
   
        1.1.1 the content and the format of the certificate of
        analysis, which exhibits actual numerical results and makes
        reference to the raw material specifications and validated test
        methods used;
   
        1.1.2 that the raw material vendor must inform the drug
        fabricator of any changes in the processing or specifications of
        the raw material and;
   
        1.1.3 that the raw material vendor must inform the drug
        fabricator in case of any critical deviation during the manufacturing
        of a particular batch of a raw material.
   
   1.2 An audit report is issued by a qualified regulatory authority demonstrating that the API fabricator complies with the ICH Good Manufacturing Practice guide for API or with any standard or system of equivalent quality. This report should be less than 3 years old, but is valid for 4 years from the date of the inspection. If such an audit report is unavailable or is more than 4 years old, an on-site audit of the API fabricator, against the same standard or its equivalent, by a person who meets the requirements of Interpretation 1 under Section C.02.006, is acceptable.
   
   1.3 Complete confirmatory testing is performed on the first lot of any raw material received from a new vendor. For API's, a copy of the results of the impurity and residual solvent profile is also obtained.
   
        1.3.1 Where the manufacturing process for an API has been
        modified, a new profile for impurity and residual solvents is
        obtained from the vendor.
   
   1.4 Identification of how re-testing failures and any subsequent re-qualification of the vendor are to be addressed.
   
   1.5 The list of raw materials not subject to the reduced testing program (e.g. reprocessed lots).
   
   1.6 Complete confirmatory testing is conducted on a minimum of one lot per year of any raw material received from each vendor, with the raw material being selected on a rotational basis.
   
   1.7 A document is issued for each vendor verifying that the vendor meets the criteria for certification. The document is approved by the quality control department and is updated at an appropriate frequency.
   
   
2. Identity testing:
   
   Specific identity testing is conducted on all lots of any raw material received on the premises of the person who formulates the raw material into dosage forms. This identity testing is performed in accordance with Regulation C.02.009, Interpretation 6.
   
   
3. Generally, due to the nature of its operations, a broker or wholesaler of raw materials cannot be directly certified. However, when the broker or wholesaler supplies materials received from the original vendor without changing the existing labels, packaging, certificate of analysis, and general information, then certification of the original source is still acceptable.
   
   
4. Provided that the identity test referred to in Interpretation 2 is performed, a lot or batch of raw material selected for confirmatory testing may be used in fabrication prior to completion of all tests with the approval of the quality control department.
   
   
5. Conditions of transportation and storage are such that they prevent alterations to the potency, purity, or physical characteristics of the raw material. In order to demonstrate that these conditions have been met, standard operating procedures and records for shipping and receiving are available and contain
   
   5.1 the type of immediate contact and protective packaging for the raw material;
   
   5.2 the labelling requirements including storage conditions and special precautions or warnings, for the packaged raw material;
   
   5.3 the mode(s) of transportation approved for shipping the packaged raw material;
   
   5.4 a description of how the packaged raw material is sealed;
   
   5.5 the verification required to ensure that each package has not been tampered with and that there are no damaged containers; and
   
   5.6 evidence that special shipping requirements (e.g., refrigeration) have been met if required.
   
   
6. Where a batch of any raw material, after leaving the site of its fabrication is handled in any substantial way (e.g., repackaged by a third party) prior to its receipt on the premises of the person who formulates the raw material into dosage forms, each container in that batch is sampled and its contents positively identified.
   
   
7. If a delivery or shipment of raw material is made up of different batches, each batch is considered as separate for the purposes of sampling, testing, and release.
   
   
8. If the same batch of raw material is subsequently received, this batch is also considered as separate for the purpose of sampling, testing, and release.
   
   However, full testing to specifications may not be necessary on such a batch provided that all the following conditions are met:
   
   8.1 a specifically discriminating identity test is conducted;
   
   8.2 the raw material has not been repackaged or re-labelled;
   
   8.3 the raw material is within the re-test date assigned by its vendor; and
   
   8.4 evidence is available to demonstrate that all pre-established transportation and storage conditions have been maintained.

Manufacturing Control

Regulation

C.02.011

1. Every fabricator, packager/labeller, distributor referred to in paragraph C.01A.003(b) and importer of a drug shall have written procedures, prepared by qualified personnel, in respect of the drug to ensure that the drug meets the specifications for use of that drug.
   
   
2. Every person required to have written procedures referred to in subsection (1) shall ensure that each lot or batch of the drug is fabricated, packaged/labelled and tested in compliance with those procedures.

Rationale

This Regulation requires that a number of measures be taken to maintain the integrity of a drug product from the moment the various raw materials enter the plant to the time the finished dosage form is released for sale. These measures seek to ensure that all manufacturing processes are clearly defined, systematically reviewed in light of experience, and shown to be capable of consistently manufacturing pharmaceutical products of the required quality that comply with their established specifications.

Interpretation

1. All handling of materials and products, such as receipt, quarantine, sampling, storage, tracking, labelling, dispensing, processing, packaging and distribution is done in accordance with approved written procedures or instructions and recorded.
   
   
2. All critical production processes are validated. Detailed information is provided in Health Canada's Validation Guidelines for pharmaceutical dosage forms.
   
   
3. Validation studies are conducted in accordance with predefined protocols. A written report summarizing recorded results and conclusions is prepared, evaluated, approved, and maintained.
   
   
4. Changes to production processes, equipment, or materials that may affect product quality and/or process reproducibility are validated prior to implementation.
   
   
5. Any deviation from instructions or procedures is avoided. If deviations occur, qualified personnel write a report that describes the deviation, the investigation, the rationale for disposition, and any follow-up activities required. The report is approved by the quality control department.
   
   
6. Checks on yields and reconciliation of quantities are carried out at appropriate stages of the process to ensure that yields are within acceptable limits.
   
   
7. Deviations from the expected yield are recorded and investigated.
   
   
8. Access to production premises is restricted to designated personnel.
   
   
9. Provided that changeover procedures are validated and implemented, non-medicinal products may be fabricated or packaged/labelled in areas or with equipment that is also used for the production of pharmaceutical products.
   
   
10. Before any processing operation is started, steps are taken and documented to ensure that the work area and equipment are clean and free from any raw materials, products, product residues, labels, or documents not required for the current operation.
    
    
11. In-process control activities that are performed within the production areas do not pose any risk to the quality of the product.
    
    
12. Measuring devices are regularly checked for accuracy and precision, and records of such checks are maintained.
    
    
13. At all times during processing, all materials, bulk containers, major items of equipment and the rooms used are labelled or otherwise identified with an indication of the product or material being processed, its strength, and the batch number.
    
    
14. Rejected materials and products are clearly marked as such and are either stored separately in restricted areas or controlled by a system that ensures that they are either returned to their vendors or, where appropriate, reprocessed or destroyed. Actions taken are recorded.
    
    
15. Equipment is located so that production operations undertaken in a common area are compatible.
    
    
16. Upon receipt, bulk drugs, in-process (intermediate) drugs, raw materials, and packaging materials are accounted for and held in quarantine until released by the quality control department.
    
    
17. Procedures are in place to ensure the identity of the contents of each container. Containers from which samples have been drawn are identified.
    
    
18. For each consignment, all containers are checked for integrity of package and seal and to verify that the information on the order, the delivery note and the vendor's labels is in agreement.
    
    
19. Damage to containers, along with any other problem that might adversely affect the quality of a material, is recorded, reported to the quality control department, and investigated.
    
    
20. Upon receipt, containers are cleaned where necessary and labelled with the prescribed data.
    
    
21. Labels for bulk drugs, in-process drugs, raw materials, and packaging materials bear the following information:
    
    21.1 the designated name of the material and a code reference where applicable;
    
    21.2 the specific batch number(s) given by the vendor and on receipt by the fabricator or packager/labeller;
    
    21.3 the status of the contents (e.g., in quarantine, on test, released, rejected, to be returned or recalled) appears on the label when a manual system is used;
    
    21.4 an expiry date or a date beyond which re-testing is necessary.
    
    Note: When fully computerized storage systems are used, backup systems are available in case of system failure to satisfy the requirements of Interpretation 21.
    
    
22. Raw materials are dispensed and verified by qualified personnel, following a written procedure, to ensure that the correct materials are accurately weighed or measured into clean and properly labelled containers.
    

    Manufacturing Master Formula

23. Processing operations are covered by master formulae, that are prepared by, and are subject to independent checks by, persons who have the qualifications described under Regulation C.02.006 Interpretation 1.
    
    
24. Master formulae are written to provide not less than 100% of label claim and include the following:
    
    24.1 the name of the product, with a reference code relating to its specifications;
    
    24.2 a description of the dosage form, strength of the product, and batch size;
    
    24.3 a list of all raw materials to be used, along with the amount of each, described using the designated name and a reference that is unique to that material (mention is made of any processing aids that may not be present in the final product);
    
    24.4 a statement of the expected final yield, along with the acceptable limits, and of relevant intermediate yields, where applicable;
    
    24.5 a statement of the principal equipment to be used;
    
    24.6 the procedures, or reference to the procedures, to be used for preparing the critical equipment, e.g., cleaning (especially after a change in product), assembling, calibrating, sterilizing, etc.;
    
    24.7 detailed stepwise processing instructions (e.g., checks on materials, pretreatment, sequence for adding materials, mixing times or temperatures, etc.);
    
    24.8 the instructions for any in-process controls, along with their limits;
    
    24.9 where necessary, the requirements for storage of the products, including the container, the labelling and any special storage conditions; and
    
    24.10 any special precautions to be observed.
    

    Packaging Master Formula

25. In the case of a packaged product, the master formula also includes for each product, package size and type, the following:
    
    25.1 the package size, expressed in terms of the number, weight, or volume of the product in the final container;
    
    25.2 a complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types with the code or reference number relating to the specifications for each packaging material;
    
    25.3 an example or reproduction of the relevant printed packaging materials and specimens, indicating where the batch number and expiry date of the product are to be positioned;
    
    25.4 special precautions to be observed, including a careful examination of the packaging area and equipment in order to ascertain the line clearance before operations begin;
    
    25.5 a description of the packaging operations, including any significant subsidiary operations and the equipment to be used; and
    
    25.6 details of in-process controls, with instructions for sampling and acceptance limits.
    

    Manufacturing Batch Document

26. Each batch processed is effectively governed by an individually numbered manufacturing order prepared by qualified personnel from the master formula by such means as to prevent errors in copying or calculation and verified by qualified personnel.
    
    
27. As it becomes available during the process, the following information is included on or with the manufacturing order:
    
    27.1 the name of the product;
    
    27.2 the number of the batch being manufactured;
    
    27.3 dates and times of commencement and completion of significant intermediate stages, such as blending, heating, etc., and of production;
    
    27.4 the batch number and/or analytical control number, as well as the quantity of each raw material actually weighed and dispensed (for active raw material, the quantity is to be adjusted if the assay value is less than 98% calculated on "as is" basis and on which the master formula was based);
    
    27.5 confirmation by qualified personnel of each ingredient added to a batch;
    
    27.6 the identification of personnel performing each step of the process; and of the person who checked each of these steps;
    
    27.7 the actual results of the in-process quality checks performed at appropriate stages of the process and the identification of the person carrying them out;
    
    27.8 the actual yield of the batch at appropriate stages of processing and the actual final yields, together with explanations for any deviations from the expected yield;
    
    27.9 detailed notes on special problems with written approval for any deviation from the master formula; and
    
    27.10 after completion, the signature of the person responsible for the processing operations.
    
    
28. Batches are combined only with the approval of the quality control department and according to pre-established written procedures.
    
    28.1 The introduction of part of a previous batch, conforming to the required quality, into the next batch of the same product at a defined stage of fabrication is approved beforehand. This recovery is carried out in accordance with a validated procedure and is recorded.
    

    Packaging Batch Document

29. Packaging operations are performed according to comprehensive and detailed written operating procedures or specifications, which include the identification of equipment and packaging lines used to package the drug, the adequate separation and if necessary, the dedication of packaging lines that are packaging different drugs and disposal procedures for unused printed packaging materials. Packaging orders are individually numbered.
    
    
30. The method of preparing packaging orders is designed to avoid transcription errors.
    
    
31. Before any packaging operation begins, checks are made that the equipment and work station are clear of previous products, documents, and materials that are not required for the planned packaging operations and that equipment is clean and suitable for use. These checks are recorded.
    
    
32. All products and packaging materials to be used are checked on receipt by the packaging department for quantity, identity and conformity with the packaging instructions.
    
    
33. Precautions are taken to ensure that containers to be filled are free from contamination with extraneous material.
    
    
34. The name and batch number of the product being handled is displayed at each packaging station or line.
    
    
35. Packaging orders include the following information (recorded at the time each action is taken):
    
    35.1 the date(s) and time(s) of the packaging operations;
    
    35.2 the name of the product, the batch number, and the quantity of bulk product to be packaged, as well as the batch number and the planned quantity of finished product that will be obtained, the quantity actually obtained and the reconciliation;
    
    35.3 the identification of the personnel who are supervising packaging operations and the withdrawal of bulks;
    
    35.4 the identification of the operators of the different significant steps;
    
    35.5 the checks made for identity and conformity with the packaging instructions, including the results of in-process controls;
    
    35.6 the general appearance of the packages;
    
    35.7 whether the packages are complete;
    
    35.8 whether the correct products and packaging materials are used;
    
    35.9 whether any on-line printing is correct;
    
    35.10 the correct functioning of line monitors;
    
    35.11 handling precautions applied to a partly packaged product;
    
    35.12 notes on any special problems, including details of any deviation from the packaging instructions with written approval by qualified personnel;
    
    35.13 the quantity, lot number, and/or analytical control number of each packaging material and bulk drug issued for use; and
    
    35.14 a reconciliation of the quantity of printed packaging material and bulk drug used, destroyed or returned to stock.
    
    
36. To prevent mix-ups, samples taken away from the packaging line are not returned.
    
    
37. Whenever possible, samples of the printed packaging materials used, including specimens bearing the batch number, expiry date, and any additional overprinting, are attached to packaging orders.
    
    
38. Filling and sealing are followed as quickly as possible by labelling. If labelling is delayed, procedures are applied to ensure that no mix-ups or mislabelling can occur.
    
    
39. Upon completion of the packaging operation, any unused batch-coded packaging materials are destroyed, and their destruction is recorded. A procedure is followed if non-coded printed materials are returned to stock.
    
    
40. Outdated or obsolete packaging materials are destroyed and their disposal is recorded.
    
    
41. Products that have been involved in non-standard occurrences during packaging are subject to inspection and investigation by qualified personnel. A detailed record is kept of this operation.
    
    
42. Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units packaged is investigated and satisfactorily accounted for before release. Validated electronic verification of all printed packaging materials on the packaging line may obviate the need for their full reconciliation.
    
    
43. Printed packaging materials are
    
    43.1 stored in an area to which access is restricted to designated personnel who are supervised by persons who have the qualifications outlined under Regulation C.02.006 Interpretation 2;
    
    43.2 withdrawn against a packaging order;
    
    43.3 issued and checked by persons who have the qualifications outlined under Regulation C.02.006 Interpretation 2; and
    
    43.4 identified in such a way as to be distinguishable during the packaging operations.
    
    
44. To prevent mix-ups, roll-fed labels are preferred to cut labels. Gang printing is avoided.
    
    
45. Cut labels, cartons, and other loose printed materials are stored and transported in separate closed containers.
    
    
46. Special care is taken when cut labels are used, when overprinting is carried out off-line and in hand-packaging operations. On line verification of all labels by automated electronic means can be helpful in preventing mix-ups. Checks are made to ensure that any electronic code readers, label counters or similar devices are operating correctly.
    
    
47. The correct performance of any printing (e.g., of code numbers or expiry dates) done separately or in the course of the packaging is checked and recorded.
    
    
48. Raw materials, packaging materials, intermediates, bulk drugs and finished products are (a) stored in locations that are separate and removed from immediate manufacturing areas, and (b) transported under conditions designated by the quality control department to preserve their quality and safety.
    
    
49. All intermediate and finished products are held in quarantine and are so identified in accordance with Interpretation 21, until released by the quality control department.
    
    
50. Every package of a drug is identified by a lot number.

Regulation

C.02.012

1. Every fabricator, packager/labeller or distributor referred to in section C.01A.003, importer, and wholesaler of a drug shall maintain
   
   
   1. a system of control that permits complete and rapid recall of any lot or batch of the drug that is on the market; and
      
      
   2. a program of self-inspection.
      
      
2. Every fabricator and packager/labeller and subject to subsections (3) and (4), every distributor referred to in section C.01A.003(b) and importer of a drug shall maintain a system designed to ensure that any lot or batch of the drug fabricated and packaged/labelled on premises other than their own is fabricated and packaged/labelled in accordance with the requirements of this Division.
   
   
3. The distributor referred to in paragraph C.01A.003(b) of a drug that is fabricated, packaged/labelled, and tested in Canada by a person who holds an establishment licence that authorizes those activities is not required to comply with the requirements of subsection (2) in respect of that drug.
   
   
4. If a drug is fabricated or packaged/labelled in an MRA country at a recognized building, the distributor referred to in paragraph C.01A.003(b) or importer of the drug is not required to comply with the requirements of subsection (2) in respect of that activity for that drug if
   
   
   1. the address of the building is set out in that person's establishment licence; and
      
      
   2. that person retains a copy of the batch certificate for each lot or batch of the drug received by that person.

Rationale

The purpose of a recall is to remove from the market, a drug that represents an undue health risk.

Drugs that have left the premises of a fabricator, packager/labeller, distributor, wholesaler and importer can be found in a variety of locations. Depending on the severity of the health risk, it may be necessary to recall a product to one level or another. Fabricators, packagers/labellers, distributors, wholesalers, and importers are expected to be able to recall to the consumer level if necessary. Additional guidance on recalls can be found in the Heath Canada document titled "Product Recall Procedures".

This Regulation also requires fabricators, packagers/labellers, distributors, wholesalers, and importers to maintain a program of self-inspection. The purpose of self-inspection is to evaluate the compliance with GMP in all aspects of production and quality control. The self-inspection program is designed to detect any shortcomings in the implementation of GMP and to recommend the necessary corrective actions.

Drugs offered for sale in Canada, regardless of whether they are domestically produced or are imported, must meet the requirements of the GMP Division of the Food and Drug Regulations. Contract production and analysis must be correctly defined, agreed on, and controlled in order to avoid misunderstandings that could result in a product or work or analysis of unsatisfactory quality. Normally, a contract or other written agreement exists between the parties involved, and that document clearly establishes the duties of each party.

Interpretation

1. A written recall system is in place to ensure compliance with Section C.01.051 of the Food and Drug Regulations and requires the following:
   
   1.1 Health Canada is to be notified of the recall.
   
   1.2 Action that is taken to recall a product suspected or known to be in violation is prompt and in accordance with a pre-determined plan; the procedures to be followed are in writing and are known to all concerned.
   
   1.3 The person(s) responsible for initiating and co-ordinating all recall activities are identified.
   
   1.4 The recall procedure is capable of being put into operation at any time, during and outside normal working hours.
   
   1.5 The recall procedure outlines the means of notifying and implementing a recall and of deciding its extent.
   
   1.6 Distribution records enable tracing of each drug product, and account is taken of any products that are in transit, any samples that have been removed by the quality control department, and any professional samples that have been distributed.
   
   1.7 Recalled products are identified and are stored separately in a secure area until their disposition is determined.
   
   1.8 The progress and efficacy of the recall is assessed and recorded at intervals, and a final report is issued (including a final reconciliation).
   
   1.9 All Canadian and foreign establishments involved in the fabrication, distribution, or importation of the recalled product are notified.
   
   
2. A self-inspection program appropriate to the type of operations of the company, in respect to drugs, ensures compliance with Division 2, Part C of the Food and Drug Regulations.
   
   2.1 A comprehensive written procedure that describes the functions of the self-inspection program is available.
   
   2.2 The program of a fabricator engaged in processing a drug from raw material through to the drug in dosage form addresses itself to all aspects of the operation. For packagers/labellers, distributors, importers, and wholesalers engaged only in packaging and/or distributing drugs fabricated by another fabricator, the written program covers only those aspects of the operations over which they exercise control on their premises.
   
   2.3 The self-inspection team includes personnel who are suitably trained and qualified in GMP.
   
   2.4 Periodic self-inspections are carried out.
   
   2.5 Reports on the findings of the inspections and on corrective actions are reviewed by appropriate senior company management. Corrective actions are implemented in a timely manner.
   
   
3. To ensure compliance of contract fabricators and packagers/labellers:
   
   3.1 All arrangements for contract fabrication or packaging/labelling and testing are in accordance with the marketing authorization for the drug product concerned.
   
   3.2 There is a written contract or other agreement covering the fabrication or packaging/labelling and/or analysis arranged among the parties involved. The contract or agreement specifies their respective responsibilities relating to the fabrication or packaging/labelling and control of the product.
   
        3.2.1 Technical aspects of the contract or agreement are
        drawn up by qualified personnel suitably knowledgeable
        in pharmaceutical technology, analysis, and GMP.
   
        3.2.2 The contract or agreement permits the distributor or
        importer to audit the facilities of the contractor.
   
        3.2.3 The contract or agreement clearly describes who is
        responsible for:
   
        - purchasing, sampling, testing, and releasing materials
   
        - undertaking production, quality, and in-process controls
   
        - process validation
   
        - test method validation
   
        3.2.4 The contract specifies the way in which the quality control
        department of the distributor or importer releasing the lot
        or batch for sale, ensures that each lot or batch has been
        fabricated and packaged/labelled in compliance with the
        requirements of the marketing authorization.
   
        3.2.5 The contract describes the handling of raw materials,
        packaging materials, in-process drug, bulk drug and finished
        products if they are rejected.
   
   3.3 The contractor's complaint/recall procedures specify that any records relevant to assessing the quality of a drug product in the event of complaints or a suspected defect are accessible to the distributor or importer.
   
   3.4 The fabricator, packager/labeller, distributor, or importer provides the contractor with all the information necessary to carry out the contracted operations correctly in accordance with the marketing authorization and any other legal requirements. The fabricator, packager/labeller, distributor, or importer ensures 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.
   
   3.5 The fabricator, packager/labeller, distributor, or importer is responsible for assessing the contractor's continuing competence to carry out the work or tests required in accordance with the principles of GMP described in these guidelines.
   
        3.5.1 Distributors of drugs fabricated, packaged/labelled
        and tested at Canadian sites are required only to have a copy
        of the relevant valid Canadian establishment licence held by the
        Canadian fabricator or packager/labeller or tester.
   
        3.5.2 Importers of drugs fabricated, packaged/labelled,
        or tested at a foreign site must meet the requirements described
        in the policy titled Conditions for Acceptance for Foreign
        Inspection Reports.

Quality Control Department

Regulation

C.02.013

1. Every fabricator, packager/labeller, distributor referred to in paragraph C.01A.003(b) and importer shall have on their premises in Canada a quality control department that is supervised by personnel described in section C.02.006.
   
   
2. The quality control department referred to in subsection (1) shall be a distinct organizational unit that functions and reports to management independently of any other functional units including the manufacturing, processing, packaging or sales unit.

Rationale

Quality control is the part of GMP concerned with sampling, specifications, and testing and with the organization, documentation, and release procedures. This Regulation ensures that the necessary and relevant tests are actually carried out and that raw materials and packaging materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory. Quality control is not confined to laboratory operations but must be incorporated into all activities and decisions concerning the quality of the product.

Although manufacturing and quality control personnel share the common goal of assuring that high-quality drugs are fabricated, their interests may sometimes conflict in the short run as decisions are made that will affect a company's output. For this reason, an objective and accountable quality control process can be achieved most effectively by establishing an independent quality control department. The independence of quality control from manufacturing is considered fundamental. The rationale for the requirement that the quality control department be supervised by qualified personnel is outlined under Regulation C.02.006.

Interpretation

1. A person responsible for making decisions concerning quality control requirements of the fabricator, packager/labeller, distributor, and importer, is on site or fully accessible to the quality control department and has adequate knowledge of on-site operations to fulfill the responsibilities of the position.
   
   
2. The quality control department has access to adequate facilities, trained personnel, and equipment in order to fulfill its duties and responsibilities.
   
   
3. Approved written procedures are available for sampling, inspecting, and testing raw materials, packaging materials, in-process drugs, bulk drugs, and finished products.
   
   
4. Quality control personnel have access to production areas for sampling and investigations as appropriate.

Regulation

C.02.014

1. No lot or batch of drug shall be made available for sale unless the sale of that lot or batch is approved by the person in charge of the quality control department.
   
   
2. A drug that is returned to the fabricator, packager/labeller, distributor referred to in paragraph C.01A.003(b) or importer thereof shall not be made available for further sale unless the sale of that drug is approved by the person in charge of the quality control department.
   
   
3. No lot or batch of raw material or of packaging/labelling material shall be used in the fabrication or packaging/labelling of a drug, unless that material is approved for that use by the person in charge of the quality control department.
   
   
4. No lot or batch of a drug shall be reprocessed without the approval of the person in charge of the quality control department.

Rationale

The responsibility for the approval of all raw materials, packaging materials and finished products is vested in the quality control department. 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 drugs and to give special attention to reprocessed drugs.

Interpretation

1. All decisions made by the quality control department pursuant to Regul