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					                       Guidance Document Submission
                                           From the BQSI committee




          Quality Management System
    For BioAnalysis Supporting Clinical Trials

                   Contributing Organizations :
      SMITHEPS

      Synomics Pharma                                           THE WETNBERG GROUP"




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Bioanalytical Quality Standards Initiative V4




                                   TABLE OF CONTENTS


1 .0    Introduction

2.0     Quality Management

3 .0    Personnel

4.0     Buildings and Facilities

5 .0    Process Equipment

6.0     Documentation and Records

7.0     Materials Management

8.0     Production and In-Process controls

9.0     Packaging, Identification and Labeling

10.0    Storage and Distribution

11 .0   Laboratory Controls

12 .0   Validation

13.0    Change Control

14.0    Rejection of Materials

15.0    Complaints and Recalls

16.0    Contracts and Agreements

17.0    Agents

18.0    Supporting Clinical Trials

19.0    Glossary




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Supporting Clinical Trials                                       Page 2 of 48
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1.0    Introduction

       The scope of the quality system should be described, consistent with 21 CFR 58 .1 and
       211.1 :

       If a charter is used, the following sections are consistent with those put forth by the ICH
       Q10, Pharmaceutical Quality System .
       Mission
       Scope
       Relationships
       Quality planning
       Resources
       Deliverables
       Communication

       ICH Q10 also indicates that a quality manual should be established.
       Quality Manual Purpose - Development of a comprehensive guidance is recommended
       in order to provide a high level overview of how the quality management system was
       developed and applied, as well as the relevant standard operating procedures (SOPs)
       developed to address the elements of the manual and how the relevant sections of the
       regulations and guidelines are applied.

       1.1 Quality Policy

       The quality policy should provide the quality objectives of the organization as well as the
       manner in which those objectives are realized.

       Quality Policy is consistent with International Standards Organization (ISO), Medicines
       and Healthcare Products Regulatory Agency (MI-IRA) and International Conference on
       Harmonization (ICH) guidelines, as well as current industry best practices .



       1.2 Organizational Description

       The following elements should be included in the organizational description:

           0   The organizational relationship to any parent company or affiliate that may
               influence, impact or contribute to the ability to do business

           0   Organizational description should include a commitment to developing or
               providing a robust disaster recovery plan, and a commitment to business
               responsibility in the event the organization departs from the business or is
               disqualified .

           0   Organizational description should include the organizations commitment to
               providing GMP/GLP compliance statements were required .


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             0   Organizational description should include the organization's commitment to due
                 diligence related to debarment.

                 The organizational description should include the companies' policies on
                 corporate governance and financial conflict of interest between the contract
                 research organization and the sponsor organization. (Part 54) .

                 Organizational description should include the reporting relationships, and process
                 for product realization.



2.0    Quality Management


       2.1       Test Facility Management Responsibilities (as per 21 CFR 58.31, 211,180)

                 This section should describe the overall responsibilities of the test facility
                 management in compliance, maintaining adequate resources for all activities, due
                 diligence in addressing non-conformances, etc . The responsibilities of the test
                 facility management should be noted as follows :

                         Assure there is a Quality Assurance Unit (QALI)
                     .   Designate a Study Director or Principal investigator; ensure the individual
                         is suitably qualified to lead the project in the area of science or
                         technology.
                         Assure appropriate SON are established and followed
                         Assure there is an Archivist.
                     .   Assure that equipment (including computer hardware and software) and
                         methods are qualified or validated as appropriate
                     0   Assure that personnel, resources, facilities, equipment, materials and
                         methodologies are available as scheduled
                         Assure personnel understand their functions and responsibilities
                     .   Assure that deviations and/or events are documented and communicated
                         and corrective and preventative actions are taken and documented .


       2.2       Quality Assurance Unit Responsibility (211.22 & 58 .35)

                 This section should describe the responsibilities of the quality assurance unit,
                 including but not limited to the following:

                         Review and approval of all quality related documents and those
                         documents that impact the accuracy or reliability of the services provided
                         Review and approval or rejection of quality records prior to release
                     0   Review and approval or rejection of specifications

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                      Review and approval or rejection of contractors or sub-contractors
                  .   Review and approval of all changes that impact the quality of services
                      provided, including those to procedures, equipment and facilities
                      Review and approval or rejection of validations and qualifications
                  .   Establishing systems for the receipt and release of materials used in
                      activities associated with performing services
                  0   Ensuring that critical deviations are investigated and corrected and that
                      internal audits are performed
                  0   Performing annual quality system reviews and assessments with
                      responsible management .


       2.3    Responsibilities of the Study Director or the Principle Investigator (58 .33)

              This section should describe the responsibilities of the study director or principle
              investigator, including:

                      Ensures all personnel engaged in the execution of the study are adequately
                      qualified (experience, training and education) for the specific duties and
                      roles.
                  0   Overall responsibility for the technical conduct of the study,
                      interpretation, analysis, documentation and reporting of results
                      Approval of the study plan and any amendments
                  .   Assures that procedures are followed and that deviations and/or events
                      are documented, and assesses the impact of deviations and/or events on
                      the quality and integrity of the study
                      Assures that the study plan, amendments and SOPs are available to the
                      study personnel
                  0   Assures that all data, including observations of unanticipated responses
                      (events) are recorded accurately and verified
                  0   Assures that unforeseen circumstances that may affect the quality and
                      integrity of the study are documented when they occur, investigated, and
                      corrective and preventative actions taken
                 0    Assures that all applicable regulatory requirements are followed (including
                      GMT and GLP, where applicable)
                      Ensures that equipment, methods and computerized systems used in the
                      study have been qualified or validated as appropriate
                      Signs the final report to indicate the acceptance of responsibility of the
                      validity of the data and the reported results
                 0    Ensures that at the completion of the study, the protocol or study plan,
                      the raw data and final report and any supporting materials (e.g.
                      communications on the interpretation of the results) are transferred to the
                      archives at the completion of the study.




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       2.3    Internal (study specific and system based) and Third Party Audits (58 .35, 58.15
              211 .180)

              This section should describe the procedures of the internal and third party audit
              program:

                  0   Auditing is completed under the auspices of quality assurance
                      management, ensuring that reports accurately reflect the elements of the
                      quality system and compliance to appropriate standards. Where serious
                      deficiencies are noted as a result of auditing, personnel are empowered to
                      notify responsible senior management .
                      Internal system audits are performed in accordance to a written schedule
                      and should cover all functional areas at least annually.
                  0   Study specific audits are conducted at a frequency that ensures the quality
                      and integrity of the study. A schedule for study specific inspections should
                      be established, based on the length of the study (e.g. once every three
                      months, twice annually, etc .) . Reports should be submitted to the Facility
                      management and the Study Director and/or Principal Investigator.
                  0   The quality assurance management is responsible for coordinating and
                      actively participating in all third party audits (these include customer,
                      regulatory or independently contracted audits). Site personnel are trained
                      on the policy and procedures for third party audits and understand their
                      responsibilities to the process . Where serious compliance deficiencies are
                      reported, senior management is notified .
                  0   All deficiencies noted during the auditing process are addressed and where
                      determined to be significant are corrected according to a written action
                      plan. The corrective and preventative action procedure is described in
                      latter sections of this document .
                  0   Periodic internal assessments (functional area audits) should be systems
                      based and consistent with current FDA practices .
                  0   The organization must make the commitment to allow regulatory,
                      sponsor and 3`d party assessment and access to all relevant records . The
                      company should have clear policies stating the limitations established with
                      respect to third party auditors (e .g. no photographs, written authorization
                      to review company specific data, etc.) .

      2 .4    Quality System Review (58 .35, 211 .180) .

             Quality Assurance management should complete a comprehensive assessment of
             the effectiveness of the quality system on an annual basis, and present the details
             of the assessment to all responsible management . This section should describe
             the steps of the quality system review.

                  0   Management actively participates in the review of the assessment, and
                      where necessary, determines if actions are required to improve
                      consistency and reliability of the system and the business output.



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                  0   A written summary of the review should be available to all organization
                      personnel.
                  0   Elements of the review should include, but not be limited to:
                          o   All items included in the management of change procedures that
                              were addressed since the last annual review;
                          o All items included in the corrective and preventative action
                            procedure that were addressed since the last annual review;
                          o   All items addressed by the customer complaint procedure over the
                              previous year;
                          o   All significant deficiencies noted during audits, including
                              regulatory, internal and 3' party audits, over the previous year;
                          o   All deficiencies related to data integrity and process reliability as
                              provided by the validation, qualification and PM/calibration
                              procedures that were encountered during the previous year.
                          o   A statistical review of the deviations and events recorded over the
                              previous year, and if trends have been identified.

        2.5   Corrective and Preventative action (820.100)

              This section should include the procedures for implementing corrective and
              preventative actions for:

                 0    Analyzing sources of quality data to identify potential causes of
                      unexpected or unforeseen circumstances, failures or other quality
                      problems
                 0    Employing appropriate statistical techniques to detect recurring quality
                      problems
                 0    Investigating the cause of nonconformities relating to processes and the
                      quality systems
                 0    Identifying the actions needed to correct and prevent recurrence of the
                      quality problems
                 0    Verifying the corrective and preventative actions are appropriate and
                      completed 'in a timely fashion .




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3.0    Personnel



       3 .1   General

              This section should describe the general personnel requirements :

                   0   Employ an adequate number of personnel that are qualified to supervise
                       and perform the services offered to customers while meeting the
                       contractual commitments for time and quality
                       Personnel qualifications obtained through a combination of formal
                       education, previous experiences and training, clearly documented and
                       current .
                       Ongoing programs exist to enhance personnel education and training
                   .   Minimum training criteria are established for all personnel, and adherence
                       to the criteria is periodically assessed (internal audits, etc .) .
                   0   Where knowledge and skills are critical to ensure accuracy and reliability,
                       proficiency is measured.
                   0   Current job descriptions and job requirements should be documented and
                       maintained .

       3.2    Qualifications (211 .25 & 58 .29)

              This section should describe the required documentation of qualifications for
              personnel:

                   0   Qualifications include curriculum vitae, certificates of participation
                       (education, training), certificates of achievement (diplomas, etc.), awards,
                       publications, etc.
                   0   Qualifications for each individual are maintained on file for the tenure of
                       the employee .
                   0   The specific responsibilities for each individual are documented, and
                       maintained on file for the duration in which the individual is engaged in
                       that role.
                   0   Procedures describing the collection and maintenance of personnel
                       qualification records have been established.

       3.3    Training (58 .29 & 58.195) .

              This section should describe the requirements and procedures for training of
              personnel :

                       Active participation in training is intrinsic to the acceptable performance
                       of the personnel.
                   0   All new employees participate in an orientation program that includes
                       training specific to performing the individual responsibilities as well as

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                      introductory training in the quality system and standards (including but
                      not limited to cGMP and GLP) .
                      On a periodic basis, training on quality standards, standard operating
                      procedures, specific regulatory requirements and quality guidelines.
                  0   All personnel routinely participate in training sessions that explore
                      regulatory requirements and current practices in the field.
                      Internal training is conducted by qualified individuals.
                      Written records of all internal training are maintained on file .
                  .   Certificates of participation are solicited, and maintained on file with the
                      training records.
                      The effectiveness of the training (Material, trainer) is demonstrated and
                      the comprehension of the trainee is determined . Training should include
                      an assessment of competence .
                      Written procedures detailing the training program are established.

       3.4    Personnel Hygiene (58 .29 & 211 .28)

              This section should describe the records and requirements for personnel hygiene:

                      Sanitation and health practices are established and are detailed . These
                      include appropriate clothing and protective equipment prescribed for
                      operating areas, ensuring the personnel are not exposed to harmful
                      materials and preventing conditions that could adversely affect the
                      integrity of materials and studies .
                  0   Specific areas are excluded from, or designated for, smoking, eating,
                      drinking, and storage of food, which are separate from the operational
                      areas.

       3.5    Consultants (211.34)

              This section should describe the requirements for the retention of consultants :

                 0    Prior to the retention of consultants, their qualifications for the specified
                      services are verified .
                      Specific procedures are established that prescribe how to collect and
                      maintain appropriate records for consultants.
                 0    Consultants' qualifications must be maintained on file.




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4.0    Buildings and Facilities

              Design and Construction (211 Subpart C; 211 .42: 58 Subpart (7; 58 .41, 47, 49, 51)

              Facilities must be adequate to ensure the integrity of the study and to prevent
              contamination of the samples and reference or control materials.
              Current and accurate diagrams or description of the facility and equipment should
              be available.

       4.1    Utilities (211 .46)

              This section should describe the utilities used:

                      Adequate, reliable power supply is necessary. Where necessary, surge
                      protection is installed to protect sensitive equipment and instruments .
                      Un-interrupted power supply (UPS) devices and back-up generators have
                      been installed where supply interruption can have a significant impact on
                      operations.
                      Laboratory ventilation systems have been designed and installed to ensure
                      that cross contamination is prevented. Areas housing sensitive equipment
                      and instruments ventilation systems with appropriate filtration units
                      (meeting ASHRAE standards) . Laboratory ventilation systems are
                      independent of study area ventilation . Where appropriate, the air is
                      conditioned (cooled, heated, humidified or dehumidified) to provide an
                      environment suitable for the operations designated for the area.
                      Current drawings of the utility systems are maintained on file.
                  .   Gasses used in conjunction with instrument operation are purchased from
                      third party qualified vendors against pre-established specifications
                      (helium, compressed air, compressed and liquid nitrogen, methane,
                      argon/methane), or manufactured on site using suitable, commercially
                      available equipment (hydrogen) .



       4.2    Water (211.48)

              This section should describe the specifications for water:

                      Water is provided by the uzater supplier, and meets the World Health
                      Organization minimum specifications for drinking (potable) water.
                      Where high purity water is required for specific operations, the "city unter"
                      is further treated by ion exd6nge and yezme asnazsis filtration. The process is
                      performed using commercially available equipment, and produces water
                      "on demand" .
                  0   Storage of purified water is diminimous ; however, the water quality is
                      periodically monitored to a written schedule to ensure suitable quality is
                      maintained .

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                  "   Where appropriate, microbial testing of water should be completed .
                  "    The purified water meets the standards of USP purified water.
                  "   Backflow prevention is in place where appropriate .

       4.3    Containment (211 .46)

              This section should describe the specifications for containment:

              Where testing or studies are conducted that use highly potent or highly toxic test
              materials (including controlled substances as regulated by the DEA), appropriate
              preventative measures should be employed and described that prevent the
              potential for contamination, cross contamination or diversion of the substances .
              These measures include special protective equipment and attire, handling and
              storage procedures and cleaning procedures to eliminate the potential for
              residues, exposure or contamination .

      4.4     Lighting (211 .44)

              This section should contain a statement regarding the lighting:

              Adequate lighting is provided throughout the facility, and is replaced or updated
              as appropriate .

      4.5     Sanitation and Maintenance, Refuse and Waste Disposal (211 .50, 211 .52, 211 .56,
              211 .58, 58 .43)

              This section should contain a description of the procedures for sanitation,
              maintenance, refuse and waste disposal:

                      Specific procedures should be in place describing the housekeeping and
                      those responsible for the housekeeping, etc ., handling of Biohazardous
                      waste, radio-labeled waste, etc .
                      Public areas, kitchen, dining area, toilet facilities and offices are cleaned
                      according to a written schedule . Cleaning methods, equipment and
                      materials are described in the schedule . Materials used are deemed to be
                      safe and present no concerns for contamination of test materials and
                      equipment.
                      Laboratories are cleaned according to written procedures. Specific
                      procedures for cleaning equipment are described in the individual
                      equipment procedures or logs.
                      The facility is maintained under the auspices of the Facilities Manager.
                 .    Refuse and waste from the public areas, toilet facilities and offices are
                      removed on a routine basis . The refuse is removed from the site.
                      Identify those responsible for removal of waste and refuse from the
                      laboratories .
                      Hazardous waste is placed in collection points generally located in the
                      laboratory, transferred to satellite accumulation points located outside the

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                      laboratory as necessary and maintained in specified storage areas until
                      removed . Hazardous waste procedures are compliant to Federal and State
                      Environmental Protection regulations .
                      Biohazardous waste is remediated either by autoclave or chemical
                      sterilization to eliminate the biohazard aspect of the materials which are
                      then treated as waste or hazardous waste.

       4.6    Pest Control (211 .56)

              This section should describe specific procedures that are in place for pest control:

                  0   Routine chemical pest control or baiting at the facility by personnel or
                      outside vendors should be described, and process in place to prevent the
                      potential for contamination of test materials and samples .
                  0   If pest control procedures are performed, all practices will be recorded by
                      the practitioner. Records will include dates of service, procedures
                      (including a list of all chemicals used) and personnel or vendor
                      performing the service .




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5.0    Equipment


       5 .1   Design and Construction (211 .63, 211 .65, 211 .105, 58 .61)

              This section should include the requirements for design and construction
              specifications :

                  0   Equipment should be suitably qualified for its intended purpose and
                      periodically undergo a qualification review.
                      Management of change procedures should be in place for all significant
                      changes to equipment, e.g. beyond "like for like" or "replacement in
                      kind,, .
                      Design qualification should be included where appropriate.
                  .   Should have equipment logs that include the best practices of GNP and
                      GLP, this includes the cleaning and maintenance schedule and procedures
                      and use logs, where appropriate.
                      Practices should be in place in order to assess the reliability of the
                      equipment, e.g. statistical review of key performance metrics .
                      Equipment is purchased against pre-established design specifications
                      (DQ that are developed to ensure that the equipment is suitable for its
                      intended use.
                 0    Pre-established design specifications give consideration to the specific or
                      general use expectations of the equipment as well as the reliability of the
                      equipment and the equipment manufacturer.
                 0    Equipment is located to facilitate the use, cleaning and maintenance of the
                      equipment, and spatially located to prevent contamination of the
                      equipment or the samples being tested on the equipment .
                      Equipment is located by use and function .
                 .    The reliability of the installed equipment is ensured by implementing the
                      accepted practices of installation, operation and performance
                      qualifications as they are applied to analytical instrumentation .
                      The specific procedures for DQ, IQ, OQ and PQ are provided in § 12 of
                      this guidance document .
                 0    Overall program to manage equipment should be described, including the
                      f ollowing:
                      o Location of the permanently installed equipment and operating
                           manuals ;
                      o   Model and Serial numbers for each component of the system;
                      o   Status of the IQ, OQ and PQ;
                      o   Calibration and Preventative Maintenance Schedule, along with last
                          calibration or PM dates and the next scheduled date ;
                      o   The name of the instrument owner, who is the individual who has
                          primary responsibility for the piece of equipment and ensuring that
                          the equipment remains in a compliance status ;



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       5 .2   Equipment Maintenance and Cleaning (211.67, 211 .182, 58.63)

              This section should include information on equipment maintenance and cleaning
              requirements :

                      Equipment logs should be employed for each piece of equipment that
                      requires the maintenance of records. Each log should include specific
                      procedures, including the methods and materials for the routine
                      inspection, cleaning, maintenance, testing, calibration and/or
                      standardization of the equipment . Procedures should be specified to
                      indicate the remedial action required for non-routine events, including
                      equipment failure . Each log should designate the individual responsible
                      for the equipment (equipment owner) . The logs should provide bound
                      sheets for recording the activities associated with the specific events listed,
                      including the non-routine activities, the remedial action taken and any
                      investigational findings along with appropriate corrective or preventative
                      measures.
                  0   Calibration and preventative maintenance procedures (where appropriate)
                      and schedules should be provided in the individual equipment logs
                      (consistent with the metrology program), and include the tolerances,
                      acceptance ranges based on either the manufacturers specifications or
                      company internal requirements . Where unique cleaning procedures are
                      required, these should be detailed in the individual equipment logs. The
                      status of any piece of equipment should be able to be readily determined
                      by referring to the specific equipment log .
                  0   Where equipment has been designated as "major", equipment use should
                      be recorded in the individual equipment logs. Each log should specify the
                      information that is recorded with each use. The metrology program
                      should specify -which pieces of equipment are considered "major" .
                  0   The specific procedures included with each of the individual equipment
                      logs should be reviewed and approved by a primary user of that
                      equipment, and preferably by the equipment owner and the functional
                      area manager . The equipment logs should be re-issued annually,
                      incorporating changes and improvements as appropriate . The previous
                      equipment logs should be held in the laboratory for one year where they
                      are readily available .

       5 .3   Calibration (58 .63)

              This section should include information on calibration requirements :

                  0   Equipment that is classified as "critical" metrology program should be
                      calibrated according to the published schedule using written procedures .
                      Calibrations should be completed using materials or standards that are
                      traceable to certified standards. Documentation tracing the materials or
                      standards should be maintained on file with the specific equipment
                      records . In instances where equipment is calibrated by outside

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                     contractors, verification of the traceability of standards is required, and
                     maintained with the specific equipment records .
                     When calibration is not performed within the prescribed time frame, the
                     piece of equipment or instrument should be tagged "out of service", and
                     not used until the calibration has been acceptably performed. Where
                     equipment is found to be "out of calibration", the status should be
                     documented in the non-routine activity log, and investigated to determine
                     the impact on the accuracy and reliability of data generated using the "out
                     of calibration" equipment. Procedures for the investigation should be
                     detailed in the specific standard operating procedure.
                     All equipment or instruments requiring scheduled calibrations should be
                     prominently labeled with the most recent calibration date, the next due
                     calibration date, and the initials of the individual affixing the label.
                     Calibration scheduled should be established based on sound scientific
                     judgment and historical results.
                 0   Where non-durable instruments (devices) are purchased and used for the
                     duration in which the calibration is effective, the devices should be
                     assessed at the end of the use period to ensure the device remained within
                     the tolerances over the life of use . These include temperature and
                     humidity measuring devices . Each device should be accompanied with a
                     calibration certificate, which is maintained on file .

       5 .4   Computerized Systems (211 .68, 58 .61)

              This section should include information on computer system requirements:

                     Systems that require computers with software operating systems in order
                     for the instrument or equipment to perform according to design
                     specifications should undergo software validation, installation and
                     operational qualification suitable to the intended purpose of the system.
                     When available, this information should be provided by the software
                     vendor at the time of installation . Where vendor validations are not
                     commercially available, internal validations follow the established
                     procedures outlined for validations .
                 0   Each system should be assigned a system administrator, who's function is
                     to set up and maintain the system, establish access controls, ensure that
                     changes to the system follow established change control procedures
                     (separate procedures addressed in § 13 of this document) and that all data
                     is preserved (including change audit trails and regular system/data
                     backups) .
                 0   Specific operation and maintenance procedures should be maintained for
                     each system, and where these are not commercially available, should be
                     detailed for the specific systems.



6.0   Documentation and Records


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       This section should describe the requirements for documentation and records . The
       Good Laboratory Practices standards, 21 CFR 58 are more prescriptive for the
       requirements pertaining to documents and records and the content and format of the
       issued work instructions (Master Production instructions for GNP and Study Protocols
       for the GLPs) than 21CFR Part 211 or ICH Q7A . Therefore, this section of the
       guideline reflects the increased emphasis on those regulatory requirements.

       6 .1   Documentation System and Specifications (211 .180, 58.81, 58 .190, 58 .195)

              0   All documents that are related to the work flow, data generation and
                  reporting, process improvement or remediation, any study or program
                  commissioned in support of a regulatory requirement or filing, or proposed
                  regulatory filing should be prepared, reviewed, approved and distributed
                  according to approved written procedures. These include, but are not limited
                  to the quality manual, relevant "Standard Operating Procedures" (SOPs),
                  Study Protocols and Reports, work instructions and forms, records and logs .
              0   Where it is appropriate, specific SOPs should be developed to explain the
                  work flow for a specific group of documents . Similarly, a separate procedure
                  should be developed that outlines the process for the preparation, review,
                  approval and distribution of validation documentation which is specifically
                  addressed in Section 12, Validation .
              0   All documents that are approved and issued should be controlled through the
                  document management system, under the auspices of the Quality Assurance
                  unit . This includes the ability to access, edit or revise documents, and
                  maintenance of the revision histories. The access and control of documents
                  should be described in detail in separate procedures .
              0   All documents and records should be maintained on file for a minimum of X
                  years, ensuring that the requirements of 21CFR Parts 58, 211 and 320 are
                  satisfied .
              0   Specific document and record retention requirements should be detailed in
                  the approved procedures for the specific category of documents and records.
                  Documents should be readily available to individuals that se the documents in
                  the execution of their specific job responsibilities .
                  Discussion of the policy for electronic signatures .

      6 .2    Equipment Cleaning and Use Records (211 .182)

              Equipment procedures and records are discussed in the preceding section of this
              manual, section 5, Equipment. In general, specific procedures should be
              developed, reviewed, approved and issued for each major piece of equipment that
              detail the maintenance, calibration, cleaning of the equipment, and the specific
              records required for the cleaning and use of the equipment. Individual equipment
              log books should be issued for each major piece of equipment; these logs should
              be reviewed and re-issued on an annual basis . All retired logs should be
              maintained according to the principles described above and detailed in the
              specific procedure .

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       6.3    Records of Materials (211.184)

                  Records of all incoming materials including, but not limited to, reagents,
                  standards, test samples, etc . should be maintained . These records include the
                  name of the supplier or vendor (providing the manufacture's name where
                  distributors are used), identity and quantity of each delivery, along with
                  appropriate identification numbers that provide for complete material
                  traceability, and the date of receipt. This information should be maintained in
                  the form of original purchase orders and the attached packing list of each
                  received delivery.
              0   Where key quality attributes are assigned to materials, these should be verified
                  prior to use of the materials.
              0   Protocol and study records should include unique identifiers (manufacturers
                  name and lot number or suppliers unique code, etc.) of any materials
                  employed or consumed in the execution of the protocol or study, providing
                  full traceability of the materials to the manufacturer or supplier . These
                  procedures should be described and detailed in separate procedures .

       6.4    Production Instructions (211 .186, 58 .120)

              0   The preparation, review, approval and issuance of production instructions
                     which includes, but is not limited to, the documentation for the execution
                     of studies, projects and protocols should be detailed in specific
                     procedures. Consistent with the requirements of 21CFR58, these
                     documents should include :
                  o      Descriptive title and statement of purpose of the study;
                  o       Identification of the test and control articles as prescribed ;
                  o       The name of the sponsor and the name and address of this facility
                          (sub-contracting activities are described in section 16 of this manual) ;
                  o       The procedure for the identification of the test system ;
                  o       A description of the experimental design or methods to be executed,
                          including methods for the control of bias;
                  o       The type and frequency of tests, analysis and the measurements to be
                          made ;
                  o       A statement of the proposed statistical methods to be used (where
                          applicable) ;
                  o       The records to be maintained ;
                  o       The date of approval of the protocol by the sponsor and the dated
                          signature of the study director.

              0   In addition to the GLP requirements, protocols should specify (or reference
                      where appropriate), as required by the GMP regulations :
                      o The major equipment to be used ;
                      o A complete list of materials to be used for the test, including any
                        special quality characteristics ;
                      o The pre-established acceptance criteria or specifications ;

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                      o   Special notations or precautions, where appropriate;
                      o Instructions for the storage or holding of samples, materials, test and
                        control articles, including time limits where appropriate;
                      o The dated signature of the quality assurance unit .

              "   Procedures specific to recording data should be detailed in standard operating
                  procedures .

              0   Changes or revisions to approved protocols should be documented along
                  with the reason for the change, signed by the study director and approved by
                  the sponsor, and maintained with the protocol . The procedure for amending
                  protocols is included in the procedure detailing the preparation, review,
                  approval and issuance of study protocols .

              " The quality assurance unit should approve each protocol prior to execution,
                 and maintain the original or a copy of the protocol on file .

       6.5    Production Records (211 .186, 211 .188, 211 .192, 58 .81)

              "   Copies of approved protocols should be issued according to the document
                  management or control procedures . Each protocol is should be assigned a
                  unique study number, which is recorded on a master schedule . This unique
                  number is provided on all documents and records required for proper and
                  complete execution of the protocol . Specific procedures should detail the
                  issuance and execution of study protocols.

              "   All deviations from established procedures are documented, significant
                  deviations (or events) that occur during the execution of the protocol or
                  study, those that could potentially affect the accuracy or reliability of the data
                  generated or the results reported for a study, are investigated as detailed in
                  separate procedures . These investigations are extended as appropriate to
                  determine the impact of the deviation or event on other studies or protocols .

              "   Unplanned events encompass all unexpected or abnormal circumstances
                  arising during the execution of studies, and based on the nature of the
                  unplanned event, may require varying levels of response. Examples of
                  unplanned events include excursions from pre-established conditions, failures,
                  obtaining unexpected results, etc. The quality system requires that the
                  unexpected event is investigated and the cause for these events is determined,
                  where possible . Where cause is identified, corrective actions are implemented
                  and preventative measures are appropriately developed and, where
                  appropriate, the impact on previous studies is evaluated . In instances where
                  the cause of the unexpected event cannot be determined (assignable cause),
                  the quality system provides a clear process for proceeding, based on sound
                  scientific principles and regulatory standards . In every instance, events are
                  fully documented, and the impact on the reliability or integrity of the quality
                  system or specific study is determined. Event management is discussed in


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                  more detail in section 8 - production controls, section 11 - laboratory
                  controls and section 19 - supporting clinical trials .

       6 .6   Laboratory Control Records (211 .194, 58.130)

              Forms and records should be prepared, reviewed and approved as an integral part
              of the study protocol preparation procedure. As such, these records are designed
              to adequately record complete data derived from all testing. Specifically, these
              records should include:
                  " An accurate and adequate description of samples, and where appropriate,
                      the quantity and date of sample receipt;
                  " Reference to each test method employed in the execution of the study
                      protocol;
                  " The weight of each sample used for each test, and reference to the
                      preparation of each reference standard, reagent and standard preparation;
                  " The results obtained from each test, and a statement of how the test
                      results compare with the established acceptance criteria ;
                  " The signature of each person who performed the test(s) and the date the
                      test was performed, as well as the dated signature of a second individual
                      showing that the original records have been reviewed for accuracy,
                      completeness and compliance .
                  " Completed forms and records should be maintained with the issued copy
                      of the study protocol . Additional records generated through the course of
                      test execution should be maintained with the executed protocol, including,
                      but not limited to :
                      "   Raw data,
                      "   graphs,
                      "   charts,
                      "   spectra,
                      "   chromatograms,
                      "   calculations used to determine results (including units, conversion
                          factors, etc.) .

       6 .7   Production Records Review (211 .192, 58.35)

              "   Specific procedures should be developed to detail the process for production
                  record review and approval. Production records are those records that are
                  generated as a result of study protocol execution.
              "   Prior to release of the executed protocol final study report, the records are
                  reviewed by the quality unit to ensure compliance with regulatory
                  requirements and standard practices and that the reported results accurately
                  reflect the raw data.
              "   The records review includes the signed and dated reports from each of the
                                  *
                  i n d'ivI duals involved *in the execution of the study and those reports prepared



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                  as a result of changes and investigations resulting from deviations, events and
                  "out of specification" results.
              "   Each final report bears the dated signature of the quality unit to indicate the
                  completed review, and a statement of how the report complies with
                  established criteria, prior to forwarding to the sponsor or customer for
                  acceptance.

       6 .8   Archives and Record Retention (58 .190 & 195, 211.180, 320.36)

              Should determine the time frame necessary to retain the records from studies .




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7.0    Materials Management (58 . Subpart F, 211 . Subpart E)

              This section should describe the management of all materials intrinsic to the
              study, e.g. samples, specimens, etc . need to be handled and controlled to ensure
              integrity and prevent mix-ups and contamination.

       7.1    General (58 .105, 211 .80, 211 .84)

              Programs and procedures should be developed to describe the purchasing, receipt
              and quarantine, evaluation for approval or rejection, storage, handling,
              disbursement and use, and retention or reverse distribution of materials used
              within the quality system . This section should outline the programs that have
              been developed to ensure full compliance to the requirements .

              In order to bridge the differences in the standards, the use of certain terminology
              within the scope of this document and the quality system must be clarified.

                  "   Materials that are obtained for the purpose of aiding in performing studies
                      or executing protocols are referred to as "supplies" . These include
                      consumable materials such as filters, solvents, apparatus, glassware,
                      packaging materials, containers, etc. Materials that are part of a study or
                      protocol for the purpose of determining the impact or effect of the
                      materials on the substance of interest are not considered supplies .
                  "   Materials that are obtained for the purpose of and are the subject of
                      evaluation or analysis are referred to as "test materials" . These test
                      materials include both purchased or client provided materials, whether in
                      a pure state, as a mixture of components, formulated samples or
                      specimens from test systems, etc .
                  "   Materials that are obtained for the purpose of assessing the impact or
                      effect of the material on the substance of interest (or test material) are
                      referred to as components . These include items such as containers and
                      closures, packaging materials, other substances (water or diluents), bulking
                      agents, etc.
                  "   Materials that are obtained for the purpose of providing a basis of
                      comparison of the test materials are referred to as controls, standards and
                      reference standards.

              All purchased materials should be purchased against agreed upon standards or
              specifications ; from suppliers that have been approved by the Quality Unit .
              Procedures for establishing those purchasing criteria should be detailed in
              separate documents. Material specifications are established based on suitability
              for use and identified key attributes (examples include moisture level in anhydrous
              solvents, or non-reactivity of utensils with components or test materials). The
              quality unit periodically assesses the performance of suppliers of critical materials .




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              Specifications for materials should be determined either by the individual or
              groups using the materials, or by study sponsors (clients), and should be
              documented in individual monographs or study protocols.

       7.2    Receipt and Quarantine (58 .47, 211 .82)

              This section should contain information regarding the receipt and quarantine of
              materials, for example:

                  0   Materials should be received into the purchasing/ receiving office, where
                      an initial inspection of the incoming deliveries should be completed.
                  0   The incoming inspection process requires that the packaging is intact and
                      in acceptable condition and the identifying shipping documentation is
                      consistent with the purchasing documents prior to accepting the receipt
                      of the delivery.
                  0   A chain of custody should be established and the movement of materials
                      from receipt documented .
                  0   Materials should undergo further inspection upon receipt into the
                      inventory center to ensure proper labeling, etc . then recorded into the
                      inventory system .
                  0   Each container should be uniquely identified, and where necessary,
                      labeled accordingly.
                      Documents accompanying the delivery and transfer of the materials
                      should be maintained according to the section describing the procedures
                      for documents and records.
                  0   Materials are not available for use until an adequate inspection is
                      completed.
                  0   Procedures specific to the receipt, inspection, labeling and logging of
                      incoming deliveries should be detailed separately.

      7 .3    Sampling and Testing (211 .84, 58 .105)

              This section should contain information on the sampling and testing of materials :

                      Where specified, materials should be tested for suitability for use prior to
                      employing in the execution of studies or protocols. These requirements
                      should be detailed either in the individual material specifications, or in the
                      protocols.
                  0   Separate areas must be established for handling and sampling of materials
                      so that the integrity of the material is maintained .
                      In each instance that a substance or material is disbursed (sampling,
                      testing or consumption for the execution of a protocol), the event should
                      be recorded. These records allow the individual containers sampled to be
                      identified .
                  0   The results of the tests must be maintained as part of the protocol or with
                      the specific material file .


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                  0   Sponsor or customer supplied materials may use the sponsor or customer
                      supplied Certificate of Analysis provided that adequate documentation is
                      provided with the sample to appropriately define the material .

       7.4    Storage, Disbursement and Use (58 .107, 211 .86)

              This section should describe the storage and use of materials:

                  0   Materials (other than supplies or consumables) should be stored according
                      to labeled or customer (or sponsor) requirements . Available storage
                      conditions include "Freezer", "Refrigerator", "Room Temperature" and
                      "Controlled Room Temperature" .
                      Storage conditions should be routinely monitored and recorded and
                      records of each condition maintained .
                  0   The storage areas should be a restricted access area, only authorized
                      personnel accessing those areas .
                      Each time a material is disbursed, the event should be recorded. The
                      individual accessing the material should record the study number for
                      which the sample is disbursed. The date and name of the individual
                      completing the log should also be recorded. The records should be
                      maintained with the materials through the life of the study and until
                      transferred to the archives .
                      Where a primary container is emptied of its contents, the container should
                      be retained until the study or protocol has been completed and the final
                      report accepted by the sponsor or client. Specific procedures for storage
                      and disbursement should be detailed in separate documents .
                  0   Controlled substances (those materials that fall within the scope of the
                      DEA authority) are subject to additional controls and records
                      requirements to ensure compliance with the appropriate regulations .
                      Access to these materials should be further restricted by storing these
                      materials in a physically secured combination lock safe . Procedures
                      specific to the handling of the controlled substances are detailed in
                      separate documents .

       7.5    Retains and Returns (211 .87, 211 .89, 211 .70, 320 .38, 320 .63)

              This section should describe the retaining, disposal and return of materials:

                      Reserve samples of materials must be retained for the life of a study.
                  .   At the completion of a study or protocol, materials should be returned to
                      the sponsor (or designated agent) or destroyed, depending on the
                      sponsors or customers instructions.
                  0   In instances where a material is returned to a study sponsor or customer, a
                      chain of custody should be established to ensure a documented trail for
                      the return is available.
                  0   Destruction of samples can proceed only after receiving written
                      confirmation from the sponsor.

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8.0    Production and In-Process Controls (58 subpart G, 211 subpart F)

       8.1    General

              Programs and procedures should be developed to describe the production work
              flow used within the canpany quality system . Most of these procedures can be
              detailed in individual documents . This section should outline the programs that
              have been developed to ensure full compliance to both GNIP and GLP
              requirements .

                  0   In general, the scope of a project is defined through discussions between
                      the Study Sponsor or Client and the appropriate crnnpayry personnel, which
                      typically includes Business Development, Operations and the Technical
                      Center.
                      Once accepted, Project Managers or Study Directors assume full
                      responsibility for the project, carrying the project to completion, and are
                      the primary contact between conpa7zy and the Sponsor . The Project
                      Manager or Study Director should have the full resources of conparry at
                      their disposal as necessary to fulfill the obligations of the business
                      agreement between aonpany and the Sponsor .
                  0   Production and Logistics should be responsible for providing and
                      scheduling technical resources as necessary to execute the laboratory
                      phases of the project.
                      Other supporting functions should be available to the Project Manger or
                      Study Director as necessary, including but not limited to the Quality Unit,
                      Reporting, Archiving, Facilities, IT, etc .

       8 .2   Operations (58 .120, 211 .100, 211 .101, 211 .105, 211 .186, 211 .188)

              This section should describe the master schedule to ensure the product
              realization, adequate resources and performance to commitment . Amendments
              and deviations for all written procedures must be described in writing, justified
              and the impact of the amendment or deviation on the study is stated .

                 0    All projects should be Protocol or Study Plan driven . The written
                      proposal should establish the project expectations between cnnparly and
                      the Sponsor, clearly identifying all regulatory requirements and project
                      deliverables .
                      Once a proposal has been accepted (approved by the Sponsor or Client)
                      the project should be assigned a unique, identifying number and added to
                      the "Master Schedule" .
                 0    Where agreed in the proposal, a formal Protocol or Study Plan should be
                      developed under the auspices of the Study Director or Project Manager
                      (required for all GLP compliant projects) . The document serves to
                      further ensure that the expectations of the study are clear, which includes,



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                     but are not limited to, the scope and objectives of the study, regulatory
                     requirements, the deliverables upon completion of the study, etc.
                 0   The Protocol should include sufficient detail to execute the study to the
                     degree required to meet the plan expectations .
                     The Protocol should be reviewed and approved by the Project Manager
                     or Study Director, Sponsor and the Quality Unit, as indicated with dated
                     signatures, prior to the execution of the study or project .
                     Once a protocol or study plan is approved, the work instruction package
                     should be prepared and issued by the Study Director or Project Manager
                     under the auspices of the Quality Unit. The workbook, or work
                     instructions, should contain a copy of the approved Protocol or Study
                     Plan, appropriate analytical procedures or specific test instructions and all
                     necessary forms for recording data collected during the execution of the
                     study. All study specific data, including chromatograms, graphs, charts,
                     certificates, deviations, event or OOS investigations, etc . should be
                     collected and maintained with the study workbook as described in written
                     procedures . When required, executions of critical steps should be
                     witnessed by a second individual, and verification provided by the dated
                     initials recorded in the workbook All entries in the workbook should be
                     legible and reviewed for accuracy and completeness at appropriate time
                     intervals by a second individual. The Study Director has overall technical
                     responsibility for the execution of the study and the *information recorded
                     in the workbook .
                 0   Any planned changes to the approved Protocol or Study Plan should be
                     provided through approved amendments. Amendments should receive
                     the same level of review and approval as the original Study Plan or
                     Protocol. Copies of approved amendments should be maintained with
                     the issued workbook or work instructions. Unplanned changes to the
                     approved Protocol or Study Plan should be addressed as deviations.
                     Deviations must be described in writing and maintained with the
                     workbook after review by the Quality Unit and the Study Director or
                     Project Manager. In every instance of change, planned and approved, or
                     unplanned, the nature of the change must be fully described, the reason
                     for the change provided, and the impact of the change on the study
                     determined . Event resolution is described in more detail in section 8 .4 .
                     All materials used during the course of executing a study should be held
                     and handled under conditions that prevent compromising the quality or
                     integrity of the materials . This includes test substances, reference
                     standards, raw materials and reagents . Procedures for the receipt and
                     release of materials are described in earlier sections of this document.
                 0   Once released, test and reference materials should be mxirnairraduntil
                     disbursed for use in the specific study.
                 0   Records should be maintained on the disbursement, use and
                     consumption, return and ultimate disposition of the materials (including
                     disposal, archival and return to the Sponsor) .




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                  "   All containers should be labeled according to detailed procedures
                      providing a complete record for the materials, and to prevent mix-up or
                      errors .

       8.3    In-Process Controls (211 .68, 211 .110, 211 .111, 211 .165, 211 .166, 58 .35, 58 .130)

              This section should describe the in-process controls that ensure reliability,
              establish stability of materials used, and sample re-analysis.

                      Instruments and equipment used in the execution of the study should be
                      qualified, maintained and calibrated against written schedules, using
                      approved procedures.
                  0   Where appropriate, instruments and methods should be further verified
                      using industry accepted practices (e.g. system suitability, calibration
                      curves, instrument self checks, check standards, etc) prior to initiating the
                      prescribed tests.
                  0   The current status (in use, clean, etc .) of major equipment should be
                      maintained in equipment logs .
                  0   When the stability of the materials used in the study needs to be
                      established, verified, or are known to have defined time limitations, the
                      protocol should specifically address the procedures required to ensure the
                      quality of those materials for the duration of the study.
                  0   When required by the GLP regulations, study specific inspections must be
                      performed at appropriate intervals during the study. These inspections
                      should be designed to ensure that the study is executed according to the
                      approved protocol or study plan, approved procedures and applicable
                      regulatory requirements .
                  0   The results of the inspections should be provided to the Study Director or
                      Project Manager as well as other responsible management.
                  0   As previously described, system audits are an integral part of the quality
                      system and should be regularly scheduled for all functional areas within
                      the business.

       8.4    Suspect Results, Events, Out of Specification Results and Out of Trend Results .
              (58 .33, 211 .100, 211 .115, 211 .165, 211 .192)

             This section should describe the procedures that address the handling of suspect
             and out of specification results. Suspect results and events must be fully
             investigated . Event resolution and notification of the sponsor should be a large
             focus of this portion of the guideline.

                  0   Procedures must be written to address handling suspect results obtained
                      during the course of laboratory testing and analysis that are consistent
                      with the FDA draft guidance document for investigating out of
                      specification (OOS) test results for pharmaceutical production .




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                  "   The guideline should be uniformly applied to both chemical analysis and
                      bioanalytical studies as well as studies that are conducted in full
                      compliance with the GLPs.
                  "   Investigating suspect results should include any unexpected or abnormal
                      circumstances that arise during the execution of the study.
                  "   In each instance, the root cause of the failure should be identified (where
                      possible) and corrective and preventative actions implemented.
                 "    The OOS procedures developed are limited to completing a diligent
                      laboratory investigation to ensure that reported results are accurate .

       8.5    Reporting Study Results (211.103, 211 .196, 58 .185)

              This section should include information about the reporting of study results.

                 0    Reporting study results to the Study Sponsor or Client is accomplished
                      under the auspices of the Study Director.
                 0    In general, draft reports should be prepared by the Study Director or
                      Project Manager and reviewed by the Quality Unit and then made
                      available for review by the Study Sponsor prior to final approval by the
                      Study Director, the Quality Unit and where specified, the Study Sponsor.
                 0    Any changes to the approved final report should be accomplished in the
                      form of an amendment which clearly states the part of the final report
                      affected by the change and the reason for the change .
                 0    Amendments should be reviewed and approved by the same authorities as
                      the original final report .
                 0    Once the final report is approved and issued to the Study Sponsor, all
                      documents specific to the study should be transferred to archives for
                      retention according to the procedures detailed in the specific SOP. These
                      documents include, but are not limited to the original approved protocol,
                      all raw data and laboratory records, deviations and amendments, and any
                      documents or correspondence related to the interpretation of the study
                      results




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9.0    Packaging and Labeling (211 .122, 211 .125, 211 .130, 58.83, 58 .105)

              The programs and procedures developed to describe labeling and identification of
              materials used within the crn~aycy quality system should be described in this
              section. These procedures can also be detailed in individual documents .

       9.1     General

                      All materials should be labeled at the time of receipt as fully described in
                      Section 7.
                      Customer samples, test materials, reference materials, etc . should be
                      logged in the materials inventory log book, and assigned a unique number.
                  0   All materials used during the study execution should be labeled according
                      to written procedures .

10.0   Storage and Distribution (Subpart H, 211 .142, 211 .150, 211.80, 58 .47, 58 .107)

              This section should describe the storage and distribution of materials.

       10.1   General

                  0   All materials intrinsic to the execution of studies should be received and
                      stored in a manner to preserve the integrity of the materials .
                  0   Storage conditions as described in the USP General Notices should be
                      maintained for the following conditions : Freezer (-25 'C to - 10 'C),
                      refrigerated (2 °C to 8 °C and controlled room temperature .
                  0   Additional storage conditions should also be available, including low
                      temperature (-90 °C to -70 °C and warm or low humidity (less than 40 %
                      relative humidity) . Records should be maintained for temperature, and
                      where required, humidity conditions in the storage areas.
                  0   A variety of monitoring mechanisms can be used, including single point,
                      min/max and continuous measuring and recording devices .
                  0   Historical records should be maintained according to procedures detailed
                      in Section 6 - Documents and Records .
                  0   Storage areas have should have restricted access, and disbursement or
                      distribution of the materials must be documented . At the termination of
                      the study, test and reference materials should either be returned to the
                      supplier, or destroyed according to established procedures.
                      The final disposition of the materials should be documented .
                      The specific activities are detailed in Section 7 - Materials Management .




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11.0   Laboratory Controls

               This section should describe the established laboratory controls.

               11 .1   General (58.130, Subpart 1, 211 .160, 211. 100)

                   0   All laboratory work performed in conjunction with project execution
                       should be guided by approved written procedures, provided by either the
                       study sponsor or client or developed internally.
                   0   All projects should be protocol or study plan driven, and all protocols
                       should be reviewed and approved by the quality unit, as well as the study
                       director and sponsor.
                       Departures from approved written procedures (protocols or study plans)
                       should be documented, explained and approved by the sponsor according
                       to written procedures or the approved protocol.
                       Where pre-established acceptance criteria are required (e.g., batch/lot
                       release, method validation, method development, etc.) the appropriate
                       specifications should be provided by study sponsors, clients or industry
                       standards.
                   0   All laboratory work should be documented at the time the work is
                       performed, and where appropriate, reviewed according to written
                       procedures .
                   0   Where test results fail to meet the established specifications or acceptance
                       criteria, sponsors should be notified in a timely manner .
                   0   Where data or test results are suspect, investigation should be initiated in
                       accordance with written procedures .
                       Primary standards and reference standards should be used where
                       appropriate; when these standards are provided by study sponsors, it is
                       the responsibility of the sponsor to provide necessary quality and source
                       information as well as appropriate storage conditions .
                   0   The QMS should take a proactive approach to event management and
                       resolution, i.e. where unexpected or abnormal circumstances arise during
                       the execution of the study. In each instance, a thorough investigation
                       should be conducted to determine the root cause of the deviation, failure
                       or "event" and corrective and preventative actions should be determined
                       and implemented .

       11 .2   Testing of Intermediates, Drug Substances and Drug Products . (58 .105, 211 .165)

                   0   Intermediates, Drug Substances and Drug Products should be tested
                       using sponsor provided methods, compendia methods or validated
                       process.
                       Where validated methods are provided by the study sponsor, the methods
                       should be demonstrated to be suitable for use in the lab (method transfer)
                       prior to utilizing the methods for testing the materials.




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                   0   Where appropriate, the results should be compared against historical data
                       at appropriate intervals in order to ensure that systems are operating
                       consistently.

       11.3    Validation of Analytical Procedures

               Analytical and Bioanalytical methods validation is discussed in section 12 .

       11.4    Certificates of Analysis (211.165)

                   0   When requested, ctmparzywill provide Certificates of Analysis for all test
                       results generated .
                   0   Unless otherwise required, Certificates of Analysis will provide the name
                       and address of the testing facility, the identity of the batch or lot, list each
                       test performed in accordance with compendia or sponsor requirements,
                       the date each test was completed (if different than the date the certificate
                       was prepared), and the results of each test listed.
                   0   Certificates of Analysis must be dated and signed by authorized personnel
                       of the quality unit .
                   0   Where crnrparry is requested to re-issue a certificate on behalf of a supplier
                       or third party broker, the certificate should include appropriate reference
                       to the material source or origin.

       11 .5   Stability monitoring of Active Ingredients and Drug Products . (58 .105, 58 .113,
               211 .166)

               This section should describe the procedures for ensuring the stability of prepared
               stocks, samples, references and control solutions .

                       Stability of solutions, reagents, stocks etc. should be determined
                       appropriate for the duration of the study.
                       Stability should be assessed consistent with the requirements as outlined
                       in the ICH guidelines Q1A(R2), "Stability Testing of new Drug
                       Substances and Products" and Q1B, "Photostability Testing of New Drug
                       Substances and Products"
                   0   Stabilitytesting should be performed according to written, approved
                       protocols that are consistent with Sponsor requirements (e.g. - in actual
                       marketing containers or simulated marketing containers, how to handle
                       out of trend results, etc .) and compliant to Federal regulations and current
                       guidelines.
                   0   Key attributes of Drug Substances and Products should be monitored to
                       assess the impact of the storage conditions .
                   0   Annual stability reports and stability commitment statements should be
                       available for Sponsors when required .
                   0   Validated statistical software programs should be used to assess the data
                       and predict shelf life for submission requests.



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                   "   Complete stability reports meeting requirements for submission should be
                       prepared and approved by the study director and the quality unit at the
                       termination of each stability protocol .

       11.6    Expiry and Retest Dating (58 .105, 58 .113, 211.137, 211 .166)

                       Procedures should be developed to provide guidelines for establishing
                       expiry dates for reference materials, standards, reagents, prepared sample
                       solutions, etc .
                   0   In general, materials maybe retested to extend the expiry date, the
                       procedures for extending expirydates should be clear.
                       Company uses best practices to provide data used in establishing expiry
                       dates and shelf life for active ingredients, drug products and a variety of
                       formulated consumer products through a fully compliant stability
                       program .
                   0   In addition, establishing the stability of sample and reference solutions is
                       an integral part of analytical and bioanalytical method validation.

       11 .7   Reserve/Retention Samples . (211 .170, 58.195, 320 .38, 320 .63)

                   0   CcmTany should maintain reserve samples for the duration of time
                       required to fully execute a study plan or protocol.
                   0   Detailed in written, approved procedures should describe how samples
                       are maintained in compliance with the regulations, e.g. who is responsible
                       for maintaining the samples (sponsor, CRO).

       11 .8   Data (58.130(e))
                  " All raw data should be recorded at the time of the activity, legibly and
                      in ink.
                   "   Critical data records, including calculations for concentrations used for
                       dilutions or standard preparations should be revi ewed in a timely
                       manner for accuracy to ensure that work p erformed is appropriate .
                   "   Computerized and automatic data collection systems should be
                       qualified, and should hav e controls in place to ensure that onl y
                       authorized personnel have access to make changes to methods and
                       procedures . Individuals who develop the methods should be
                       indentified, and the individuals setting up the methods and running the
                       methods (e .g . loading sample sets, inputting standard and QC
                       concentrations, etc .) should be indentified in the reports generated by
                       the systems . All changes to the computerized methods used in data
                       collection systems should identify the individual making the change
                       and the reason for the change. The changes should not obscure the
                       original method.
                   "   All deviations from procedures, methods and protocols should be
                       detailed in the raw d ata and reviewed and authorized by the study



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                      director . The reason for the deviation should be pr ovided along with
                      the estimated impact or outcome on the study .
                  0   Laboratory records should be detailed and accurate enough to
                      completely reconstruct the activities of the stud y. Any changes to the
                      recorded data should be made so as not to obscur e the original data,
                      should indicate the individual m aking the change and the reason for the
                      change. All changes should be easily traceable to the original data or
                      information .




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12.0   Validation

       12.1   General

       This section should describe the overall validation policy and commitment to validations
       and qualifications . This section should also include the section from Part 820 for design
       development if the organization is involved in development of methods and processes.

                    0   Equipment, methods and computerized systems must be suitable for the
                        intended purposes, and suitability should be established through
                        prospective validation and routine re-validation of the processes .
                        Validations and re-validations should be executed under the auspices of
                        the Quality Unit, and may be performed by suitably qualified outside
                        contractors, or by company personnel.
                    0   Validations should be performed under the guidance of written protocols
                        that provide pre-established acceptance criteria .
                    0   At the completion of each validation, the performance of the system
                        against the established criteria should be summarized in a written
                        validation report .
                    0   When changes to the systems affect the performance against the key
                        attributes, the systems must be re-validated .

       12.2   Equipment Validation (211 .168, 211.100)

                    0   Industry best practices of Installation, Operation and Performance
                        Qualifications should be prospectively performed on all quality critical
                        equipment .
                    0   When performed internally, written protocols with specific test scripts
                        should be developed to guide the execution of the qualification process,
                        providing the established criteria for acceptance.
                    0   Performance qualifications should be performed to the limits of actual
                        operating conditions, e.g. stability chambers are temperature and humidity
                        mapped under use load and conditions specified by the ICH storage
                        stability guideline Q1A (R2), for refrigerated, long term and accelerated,
                        where applicable .
                    0   When appropriate, new equipment can be qualified bythe OEM (original
                        equipment manufacturer) or other suitably qualified contractor using
                        established protocols .
                        In every instance, the equipment qualifications should be performed
                        under the auspices of the Quality Unit and qualifications approved by the
                        QU and the area manger before placed into service.

       12.3   Method Validation (211 .165, 211 .113, 211 .194)

                    "   Analytical and Bioanalytical methods should be developed and validated
                        according to published standards and guidelines (USP Q225 >, ICH Q2


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                      (R1) and FDA Guidance for Industry Bioanalytical Method Validation,
                      resp .).
                  0   Methods should be validated using default standard operating procedures
                      or procedures provided by clients or sponsors as outlined in approved
                      proposals .
                  0   In every instance, written validation protocols should be developed,
                      providing pre-established acceptance criteria based on sponsor
                      requirements or industry best practices .
                      Validated methods that are transferred from other laboratories (by
                      sponsors or clients) must be subjected to transfer validation, qualifying
                      the testing lab and verifying the method performance against quality
                      critical criteria . As with original method validations, the transfer
                      validations should be conducted according to approved, written
                      protocols .
                 0    Validated procedures should be used for all testing that is intended for
                      submission in support of registrations . Where methods are used in the
                      conjunction with storage stability studies, the validation ensures that
                      methods are stability indicating .

       12.4   Computer Systems Validation

                      Must have validated computerized systems that include the hardware and
                      software for the intended use .
                 0    Where data and records are quality critical, computerized systems should
                      be validated and have an audit trail (revision or change tracking) .
                      Computerized systems should be validated using the protocols or test
                      scripts developed by the manufacturer or by the organization testing the
                      quality critical attributes .
                 0    Changes to computerized systems (e.g. software upgrades, addition of
                      new components to instruments) should be re-validated as required and
                      described in specific standard operating procedures .




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13.0   Change Control

       13.1    General (58 .81, 58.120, 211 .100, 211 .68)

                       A formal system for Change Control or Management of Change should
                       be developed for all changes that could potentially impact the accuracy or
                       reliability of data or reported results .
                       Management of change to procedures should be described in standard
                       operating procedures specific to the type of procedure .
                   0   Change to facilities, support systems, utilities, equipment and
                       computerized systems should be detailed in a procedure describing the
                       appropriate review and approval required (as well as any validation or re-
                       validations required) to implement the change .
                       Key elements included in the change control system should include the
                       verification that the change satisfies the intended purpose, revising
                       documents associated with the systems changed, and ensuring appropriate
                       training is provided to all individuals affected by the change .
                   0   Replacement in kind, or like for like change should not require the same
                       level of review as change to different design specifications .
                   0   Change history and revision history for procedures should describe the
                       change and the reason for the change .

14.0   Rejection and Re-use of Materials

       14 .1   General (58 .105, 211 .115, 211 .87, 211 .89, 211 .165)

                       Written procedures should describe the actions required when materials
                       tested do not meet the pre-established acceptance criteria .
                   0   Sponsors and clients should be notified when out of specification or out
                       of trend results are obtained and verified .
                   0   Retesting of samples to verify the out of specification or out of trend
                       result should be described in specific procedures .
                   0   Raw materials and reference materials must be verified to ensure
                       suitability for use, where appropriate .
                   0   Where these materials are rejected, they must be segregated from use until
                       returned or disposed .




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15.0   Complaints and Recalls

       15.1   General (211.198)

              This section should describe the company policy regarding customer comment
              and feedback.

                  0    Formal procedures should be developed detailing the process for
                       capturing and resolving alleged deficiencies .
                       These procedures should include review of all alleged deficiencies by the
                       Quality Unit, and Executive Management to ensure appropriate remedial
                       actions are undertaken .
                  0    Complaints should be routinely monitored to determine if trends or shifts
                       is business practices are impacting the perceived or actual quality of the
                       services provided .
                       A formal recall procedure should be developed, detailing the actions
                       required when incorrect or faulty data has been issued to sponsors or
                       clients in the form of a report or Certificate of Analysis . The procedure
                       should detail how communication with affected sponsors or clients are
                       documented and tracked to ensure that due diligence is performed in
                       notification.

16.0   Contracting (58 .10)

              This section should address contracts, the use of subcontractors, and conflicts of
              interest.

       16.1   General

                       Expectations should be clearly established between cwpany and the
                       Sponsor at the proposal stage of the process, including specific regulatory
                       compliance requirements, communication frequency, timelines,
                       deliverables, reporting requirements, etc.
                  0   Formal procedures for developing the proposal should be detailed in a
                      standard operating procedure.

       16.2   Sub-contracting
                  "   Written procedures should be developed to address the use of sub-
                      contractors contributing to the data or results in studies .
                  "   Procedures should describe how and when the sponsor is notified of the
                      use of sub-contractors and how the sub-contractor is identified, and the
                      specific role of the sub-contractor in the study.
                  "   Written procedures should describe the process that the company uses to
                      perform due diligence in verifying the subcontractor's ability to perform
                      the work to the quality standards and timelines certified by the company,
                      and the contingency plans the company has developed in the event of
                      sub-contractor failure to perform .


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                   "   Sub-contractors should the company and the sponsor to inspect the
                       facility as necessary to verify capabilities

       16.3    Financial Interests Disclosure (21CFR54)

                   "   Company should have written procedures describing the process for
                       disclosing the financial interests of the responsible scientist or study
                       director and the executive management with the sponsor or sponsor study
                       under investigation.

17.0   Agents and Brokers

               This section should describe the use of agents and brokers, and how the company
               ensures they are accurately represented.

18.0   Supporting Clinical Trials

       18 .1   General

                   0   Bioanalysis for clinical trials should be conducted in full compliance with
                       the GLP for non-clinical trials (21CF'R58) and the FDA guidance
                       documents for Bioanalytical method validation .
                   0   Chemical analysis supporting clinical trials should be conducted in
                       accordance with the FDA guidance documents for Phase 1 trials for
                       cGMP for Drug Products and the ICH guidelines for APIs .

       18 .2   Bioanalysis

                   0   Bioanalytical studies for pharmaceuticals supporting clinical and pre-
                       clinical trials should be executed in accordance with 21CFR58, GLP for
                       pre-clinical trials .
                   0   The QU should have regulatory oversight responsibility in conjunction
                       with the Study Director to assure full compliance to the GLP regulations .
                       Procedures should be developed to support clinical and pre-clinical trials
                       that are consistent with the FDA Guidance for Industry - Bioanalytical
                       Method Validation, May 2001, and the Workshop/Conference Report
                       from the Yd AAPA/FDA Bioanalytical Workshop, Validation and
                       Implementation : Best Practices for Chromatographic and Ligand Binding
                       Assays, published Feb . 2007.
                       Validatable methods should be developed using best practices and current
                       technology for tandem Mass Spectroscopy instrumentation, or other
                       appropriate instruments as required.
                       Methods used to support clinical trials should be further validated using
                       written Standard Operating Procedures for Bioanalytical Method
                       Validation that clearly describe a comprehensive process that ensure
                       methods are accurate and reliable .


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                      Staff should be trained on the methods during the development and
                      validation phases, equipment is qualified prior to the validation process .
                  0   Protocols should be developed for each study, in conjunction with the
                      Sponsor and the other facilities involved in the overall execution of the
                      study, taking into account the requirements specific to the study, e.g.
                      sample retain or archive requirements that may be different from
                      established internal procedures .
                      Consistent with the current best practices, the conpaYry should describe in
                      written procedures the number of repeat samples for Bioanalysis of
                      incurred samples (samples obtained from the dosed subject), ensuring
                      method and sample reliability throughout each batch process (typically
                      referred to as "incurred sample re-analysis") .
                 0    The number of samples and the criteria for selection for repeat analysis
                      should be determined in advance of the run (typically 5 to 10 % of the
                      total number of samples), and should be based on the overall sample size,
                      as well as a minimal threshold number of samples for smaller batch sizes.
                      Procedures should be developed to ensure consistent handling of events,
                      i.e. any unexpected or abnormal circumstances arising during the
                      execution of the study. These would include, but would not be limited to,
                      situations where the method validation or Bioanalytical run did not meet
                      the pre-established criteria, equipment failed for any cause, analyst error
                      during sample preparation or run execution, etc . In each instance, the
                      root cause of the failure should be identified (where possible) and
                      corrective and preventative actions implemented . Event resolution and
                      management should be described in detail in standard operation
                      procedures and elsewhere in this document .
                 0    Standard procedures should be developed to ensure consistent practices
                      for Bioanalytical sample reassay, consistent with the principles outlined in
                      the AAPS/FDA workshop report . Sponsor requests for reassay of
                      Bioanalytical samples should be fully justified in writing prior to the
                      reassay of samples . Reports should clearly indicate which samples have
                      been submitted for reassay and which results are included in the report.
                 0    Consistent with the GLP requirements, studies should be inspected at
                      intervals adequate to assure the integrity of the study. The inspections
                      should be documented and reported to the mnpany Study Director or
                      Principle Investigator and analytical facility management as well as the
                      protocol Study Director (when different from the principle investigator) .
                 0    Where it is intended that the results from the bioanalytical study are
                      reported prior to the completion of the study (e.g. the long term storage
                      stability component of the method validation may terminate up to 6
                      months after the bulk of the study is completed), the protocol and the
                      final report should both clearly state the portions of the study to be
                      completed and the anticipated date of completion. All data and results
                      obtained after the final report is issued should be reported by amendment
                      to the final report .

       19.3   Chemical Analysis


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                  0   Chemical analysis of active pharmaceutical ingredients and finished
                      dosage forms intended for phase 1 clinical trials must be conducted in
                      accordance with the FDA Guidance for Industry, INDs- Approaches to
                      Complying with CGMP during Phase 1, January 2006 .
                  .   Projects should be detailed in sponsor approved protocols in accordance
                      to the procedures outlined in this document, all laboratory data and
                      records should be maintained as described herein, final reports should be
                      reviewed and approved by the Quality Unit.
                  0   Whereas analytical methods do not need to be validated to the extent
                      required for commercial batch release, methods should be reliable and
                      accurate; all reports (including Certificates of Analysis) should clearly
                      indicate the extent that the analytical methods have been validated .
                 0    Chemical analysis for active pharmaceutical ingredients and finished
                      dosage forms intended for phase II and III clinical trials should be
                      conducted in accordance with 21CFR211 cGMP for Drug Products and
                      the ICH Q7A guidelines for active pharmaceutical ingredients .


              Notes - Teva requires all CRO's to use a minimum of 10 % of samples for
              the incurred sample re-analysis, regardless of the sample size of the study,
              and recommends that this is incorporated as a specific criteria into this
              standard .




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19.0    Glossary


ASHRAE
American Society of Heating, Refrigerating and Air-Conditioning Engineers - establishes
industry standard pertaining to environmental controls and systems.
Acceptance Criteria
Numerical limits, ranges, or other suitable measures for acceptance of test results .
Active Pharmaceutical Ingredient (API) (or Drug Substance)
Any substance or mixture of substances intend ed to be used in the manufacture of a drug
(medicinal) product and that, when used in the pro duction 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 a ffect the structure and function of th e body.

Amendment
An amendment is a change to a written, approved protocol or final report for the purpose of
correcting or improving the original document.
API Starting Material
A raw material, intermediate, or an API that is used in the production of an API and that is
incorporated as a significant structural fragment into the structure of the API . An API
Starting Material can be an article of commerce, a material purchased from one or more
suppliers under contractor commercial agreement, or produced in-house . API Starting
Materials are normally of defined chemical properties and structure .
Auditing
A systematic check or assessment of the effectiveness of the organization to the compliance
or conformance to the established procedures, process or regulations .
Batch (or Lot)
A specific quantity of material produc ed in a proc ess or series of pro cesses s o that it is
expected to be homogeneous within specified limits . In the case of continuous production, a
batch may correspond to a defined fraction of the production. The batch si ze can be defined
either by a fixed quantity or by the amount produced in a fixed time interval .

Batch Number (or Lot Number)
A unique combination of numbers, letters, and/or symbols that identifies a batch (or lot) and
from which the production and distribution histor y can be determined .
Bio burden
The level and type (e.g. objectionable or not) of m icro-organisms that can be present in raw
materials, API starting materials, intermediates or APIs . Bio burden should not be considered
contamination unless the levels have be en exceeded or defined objectionable organisms have
been detected .


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CFR
Code of Federal Regulations (Federal Law)
Calibration
The demonstration that a particular instrument or device produces results within specified
limits by comparison with those produced b y a reference or traceable standard over an
appropriate range of measurements .

Chain of Custody
A record that documents the transfer of materials between groups, both intra-company and
inter-company .

Computer System
A group of hardware components and associated software designed and assembled to perform
a specific function or group of functions .

Computerized System
A process or operation or instrument integrated with a computer system.

Containment
Measures taken to restrict the spread of highly hazardous substances, e.g. cytotoxic drug
substances or products, outside the desig nated work environment .
Contamination
The undesired introduction of impurities of a chemical or microbiological nature, or of
foreign matter, into or onto a raw material, intermediate, or API during production, sampling,
packaging or repackaging, storage or transport .

Contract Manufacturer
A manufacturer performing some aspect of manufacturing on behalf of the original
manufacturer.
Controlled Substances

Substances listed in the schedules provided in 21 CFR1308, and regulated by the US Drug
Enforcement Agency (DEA)
Critical
Describes a process step, process condition, test re quirement, or other relevant parameter or
item that must be controlled within predeterm ined criteria to ensure that the API or Drug
Product meets its specification .

Cross-Contamination
Contamination of a material or product with anoth er material or product.
DEA
United States Drug Enforcement Agency, authorized by the regulations provided in 21
       CFR1300 .




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DQ
Design Qualification, establishing design specifications based on the intended utility of the
item or system .
Deviation
Departure from an approved instruction or establi shed standard.
Drug (Medicinal) Product
The dosage form in the final immediate packaging intended for marketing . (Reference QlA)
Drug Substance
See Active Pharmaceutical Ingredient
Equipment Owner
The individual identified as responsible for the continued acceptable performance of the
assigned equipment, including assuring that instrument is routinely serviced and calibrated to
pre-established criteria.
Event
An unusual or unexpected circumstance arising during the course of normal operations .
Events include, but are not limited to the following examples: unexpected experimental
results (out of trend, out of specification), erratic performance or failure of equipment,
excursions or deviations from established conditions or procedures, etc .
Expiry Date (or Expiration Date)
The date placed on the container/labels of an API designating the time during which the API
is expected to remain within established shelf life specifications if stored u nder defined
conditions, and after whi ch it should not be used .
GCP
Good Clinical Practices - a collection of regulations and guidance documents that for the set
of rules for conducting clinical trials .

GLP
Good Laboratory Practices (see 21CFR58)
cGMP
current Good Manufacturing Practices (see 21CFR 210/211)

ICH
International Conference on Harmonization, a world wide consortium of experts designed to
harmonize the varying national standards .

IQ
Installation Qualification - A formal action of proving and documenting that equipment or
ancillary systems are properly installed as designed and for the intended purpose.




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IND
Investigational New D rug

Impurity
Any component present in the interm ediate or API that is not the desired en tity.
Impurity Profile
A description of the ident ified and unidentified im purities present in an AP I.
In-Process Control (or Process Control)
Checks performed during production in order to m onitor and, if appropri ate, to adjust the
process and/or to ensure that the intermediate or API conforms to its specifications .
Intermediate
A material produced during steps of the processing of an API that undergoes further
molecular change or purification before it becomes an API . Intermediates mayor may not be
isolated . (Note : this Guide onl y addresses those intermediates produced after the point that
the company has defined as the point at which the production of the AP I begins .)
Lot
See Batch
Lot Number
See Batch Number
Manufacture
All operations of receipt of materials, production, packaging, repackaging, labeling, re-
labeling, quality control, release, storage, and distribution of APIs and related controls .
Management of Change
A formal process for documenting and assessing the impact of change and providing
processes and procedures to address that change with affected individuals . Management of
change includes elements of qualification, ch ange notification, training, etc .

Master Schedule
A comprehensive list of all laboratory studies conducted at the testing facility indexed by test
article and containing the test system, nature of study, date study was initiated, current status
of each study, identity of the sponsor, and name of the study director.
Material
A general term used to denote raw materials (starting materials, reagents, and solvents),
process aids, intermediates, APIs and packaging and labeling materials .

OECD
Organisation for Economic Co-operation and Development - The Organisation for Economic
Co-operation and Development (OECD) is an intergovernmental organisation in which
representatives of 29 industrialised countries in North America, Europe and the Pacific, as
well as the European Commission, meet to co-ordinate and harmonize policies, discuss issues
of mutual concern, and work together to respond to international problems . Most of the


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OECD's work is carried out by more than 200 specialised Committees and subsidiary groups
composed of Member country delegates . Observers from several countries with special status
at the OECD, and from interested international organisations, attend many of the OECD's
Workshops and other meetings . Committees and subsidiary groups are served by the OECD
Secretariat, located in P aris, France, which is organised into Directorates and Divisions .
OOS Results
"Out of Specification" Results, as described in the FDA guidance for industry "Investigating
Out of Specification (O OS) Test Results for Pharmaceutical Production, the term OOS results
includes all suspect resul ts that fall outside the specifications or a cceptance criteria
established in new drug applications, official compendia, or b y the manufacturer .

OQ

Operational Qualification - A formal process or action of proving and documenting that
equipment or ancillary systems work correctly (OQ as designed or as intended for purpose.

PM
Preventative Maintenance - scheduled periodic maintenance to prevent instrument or machine
failure .
PQ
Performance Qualification - A formal process or action of proving and documenting that
equipment or ancillary systems actually lead to the expected results (PQ)
PV
Performance Verification - A formal process or action of providing and documenting that
equipment or ancillary systems actually lead to the expected results .

Packaging Material
Any material intended to protect an intermediate or API during storage and transport .
Procedure
A documented description of the operations to be performed, the precautions to be taken and
measures to be applied directly or indirectly related to the manufacture of an intermediate or
API .
Process Aids
Materials, excluding solvents, used as an aid in the manufacture of an intermediate or API that
do not themselves participate in a chemical or biological reaction (e.g. filter aid, activated
carbon, etc) .
Process Control
See In-Process Control




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Production
All operations involved in the prepa ration of an API from receipt of materials through
processing and packaging of the API .
Protocol
The detailed written plan for the scientific experiment, trial or other intended research,
designed to ensure the regulatory elements or industry standards relevant to the experiment or
study are addressed.
QMS
Quality Management Systems

Qualification
Action of proving and documenting that equipment or ancillary systems are properly installed
(IQ), work correctly (OQ), and actually lead to the expected results (P Q. Qualification is
part of validation, but the individual qualification steps alone do not constitute process
validation .
Quality Assurance (QA)
The sum total of the organized arrangements made with the object of ensuring that all APIs
are of the quality required for their intended us e and that quality systems are maintained .
Quality Control (QC)
Checking or testing that specifications are met .
Quality Unit(s)
An organizational unit independent of p roduction which fulfills both Quality Assurance and
Quality Control responsibilities . This can be in the form of separate QA and QC units or a
single individual or group, depending upon the size and structure of the organization .
Quarantine
The status of materials isolated physically or by other effective means pending a decision on
their subsequent approv al or rejection .
Raw Data
Original data, recorded either manually or by electronic systems .
Raw Material
A general term used to denote starting materials, reagents, and solvents intended for use in the
production of intermediates or APIs .
Reference Standard, Primary
A substance that has b een shown b y an extensive set of anal ytical tests to b e authentic
material that should be of high purity . This standard can be: (1) obtained from an officially
recognized source, or (2) prepared by independent synthesis, or (3) obtained from existing
production material of high purity, or (4) prepared by further purification of existing
production material .




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Reference Standard, Secondary
A substance of established quality and purity, as shown by comparison to a primary reference
standard, used as a reference standard for routine laboratory analysis.
Reprocessing
Introducing an intermediate or API, including one that does not conform to standards or
specifications, back into the process and repeating a crystallization step or other appropri ate
chemical or physical manipulation steps (e.g ., distillation, filtration, chrom atography, milling)
that are part of the established manufacturing process. Continuation of a process step aft er an
in-process control test has shown that the step is incom plete is considered t o be part of the
normal process, and not reprocessing .

Retest Date
The date when a material should be re-examined to ensure that it is still sui table for use.
Reworking
Subjecting an intermediate or API that does not conform to standards or sp ecifications to one
or more processing steps that are different from the established manufacturing process to
obtain acceptable qualit y intermediate or API (e.g., recrystallization with a different solvent).

Signature (signed)
See definition for si gned
Signed (signature)
The record of the individual who performed a particular action or review . This record can be
initials, full handwritten signature, personal seal, or authenticated and secure electronic
signature .
Solvent
An inorganic or organic liquid used as a vehicle for the preparation of solutions or
suspensions in the manufacture of an intermediate or API .
Specification
A list of tests, references to analytical procedures, and appropriate acceptance criteria that are
numerical limits, ranges, or other criteria for the test described . It establishes the set of
criteria to which a material should conform to be considered acceptable for its intended use.
"Conformance to specification" means that the material, when tested according to the listed
analytical procedures, will meet the listed acceptance criteria .
Study Plan
The detailed research plan for the scientific experiment.

Validation
A documented program that provides a high degree of assurance that a specific process,
method, or system will consistently produce a result meeting pre-determined acceptance
criteria.




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Validation Protocol
A written plan stating how validation will be conducted and defining acceptance criteria . For
example, the protocol for a manufacturing process identifies processing equipment, critical
process parameters/operating ranges, product characteristics, sampling, test data to be
collected, number of validation runs, and acceptable test results .               ,




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                                  Committee Participants

Leonore Witchey ; Generamedix
Marty Joyce, Generamedix
Brian Schuster; Perrigo
Sethu Kavuri ; Perrigo
Nageshwar Thudi; Ranbaxy
Tausif Monif ; Ranbaxy
Kirk Smith; The Smithers Group
John Pirro ; Synomics Pharmaceutical Services, LLC
Hope Aubin ; Synomics Pharmaceuticals, LLC
Karen Otrupchak; Teva
Greg DeRosa ; Teva
     ;
Joel Fall The Weinberg Group
Keith Gallicano ; Watson
Bang Xu, Watson
Jack Garvey - Compliance Architects




Guidance Document Submission - Quality Management System For BioAnalysis
Supporting Clinical Trials                                      Page 48 of 48

				
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Description: Quality Management in Clinical Trials document sample