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Guidance Document Submission From the BQSI committee

Quality Management System For BioAnalysis Supporting Clinical Trials

Contributing Organizations :

SMITHEPS

Synomics Pharma

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THE WETNBERG GROUP"

Version 4

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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

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


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:

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

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 .

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



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 :

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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 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 :

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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 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 Ensuring that critical deviations are investigated and corrected and that internal audits are performed 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 :

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Ensures all personnel engaged in the execution of the study are adequately qualified (experience, training and education) for the specific duties and roles. 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 Assures that all data, including observations of unanticipated responses (events) are recorded accurately and verified 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 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 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.



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:

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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. 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. 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 . 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 . Periodic internal assessments (functional area audits) should be systems based and consistent with current FDA practices . 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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A written summary of the review should be available to all organization personnel . 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:

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



3.0 Personnel

3 .1 General

This section should describe the general personnel requirements :

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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 .) . Where knowledge and skills are critical to ensure accuracy and reliability, proficiency is measured. 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 :

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Qualifications include curriculum vitae, certificates of participation (education, training), certificates of achievement (diplomas, etc.), awards, publications, etc. Qualifications for each individual are maintained on file for the tenure of the employee . The specific responsibilities for each individual are documented, and maintained on file for the duration in which the individual is engaged in that role . 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:

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Active participation in training is intrinsic to the acceptable performance of the personnel . 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 . 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:

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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 . 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 :

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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 . Consultants' qualifications must be maintained on file .



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 :

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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:

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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" . Storage of purified water is diminimous; however, the water quality is periodically monitored to a written schedule to ensure suitable quality is maintained .



" 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:

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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



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 :

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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 . 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 .



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 :

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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 . 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. 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 . 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 ;



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

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

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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 . 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 . 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" . 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. 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:

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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 . 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) . 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



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)

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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 f orms, records and logs . 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 . 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 . 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 . 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 .



6.3 Records of Materials (211.184)

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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. Where key quality attributes are assigned to materials, these should be verified prior to use of the materials . 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)

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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.

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 .

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



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 d' I inv n iv duals * olved *in the execution of the study and those reports prepared



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 .



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 .



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:

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Materials should be received into the purchasing/ receiving office, where an initial inspection of the incoming deliveries should be completed . 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. A chain of custody should be established and the movement of materials from receipt documented . Materials should undergo further inspection upon receipt into the inventory center to ensure proper labeling, etc . then recorded into the inventory system . 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. Materials are not available for use until an adequate inspection is completed. 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 :

0

0

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. 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 . The results of the tests must be maintained as part of the protocol or with the specific material file .



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

0

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 . 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. 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:

.

0

0

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 . 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. Destruction of samples can proceed only after receiving written confirmation from the sponsor.



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 can pany 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

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 con parry at their disposal as necessary to fulfill the obligations of the business agreement between aonpany and the Sponsor . 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

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" . 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,



0

0

0

0

but are not limited to, the scope and objectives of the study, regulatory requirements, the deliverables upon completion of the study, etc. 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 . 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. Once released, test and reference materials should be mxirnairraduntil disbursed for use in the specific study. 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) .



" 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 .

0

0

0

0

0

0

Instruments and equipment used in the execution of the study should be qualified, maintained and calibrated against written schedules, using approved procedures. 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. The current status (in use, clean, etc .) of major equipment should be maintained in equipment logs . 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. 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 . The results of the inspections should be provided to the Study Director or Project Manager as well as other responsible management. 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 .



" 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

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0

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0

Reporting study results to the Study Sponsor or Client is accomplished under the auspices of the Study Director. 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. 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 . Amendments should be reviewed and approved by the same authorities as the original final report . 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



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

0

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. 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

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All materials intrinsic to the execution of studies should be received and stored in a manner to preserve the integrity of the materials . 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 . 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 . A variety of monitoring mechanisms can be used, including single point, min/max and continuous measuring and recording devices . Historical records should be maintained according to procedures detailed in Section 6 - Documents and Records . 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.



11.0 Laboratory Controls

This section should describe the established laboratory controls .

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

0

0

0

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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. 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 . All laboratory work should be documented at the time the work is performed, and where appropriate, reviewed according to written procedures . Where test results fail to meet the established specifications or acceptance criteria, sponsors should be notified in a timely manner . 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 . 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 .



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)

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0

When requested, ctmparzywill provide Certificates of Analysis for all test results generated . 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 . Certificates of Analysis must be dated and signed by authorized personnel of the quality unit . 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 .

0

0

0

0

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" 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 . Key attributes of Drug Substances and Products should be monitored to assess the impact of the storage conditions . Annual stability reports and stability commitment statements should be available for Sponsors when required . Validated statistical software programs should be used to assess the data and predict shelf life for submission requests .



" 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)

0

0

Procedures should be developed to provide guidelines for establishing expiry dates for reference materials, standards, reagents, prepared sample solutions, etc . 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 . 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

0

CcmTany should maintain reserve samples for the duration of time required to fully execute a study plan or protocol. 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


Sioanalytical Quality Standards Initiative V4

0

director . The reason for the deviation should be pr ovided along with the estimated impact or outcome on the study. 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 .



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

0

0

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. Validations should be performed under the guidance of written protocols that provide pre-established acceptance criteria . At the completion of each validation, the performance of the system against the established criteria should be summarized in a written validation report . 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)

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0

Industry best practices of Installation, Operation and Performance Qualifications should be prospectively performed on all quality critical equipment . 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 . 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 . 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



0

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0

(R1) and FDA Guidance for Industry Bioanalytical Method Validation, resp .) . Methods should be validated using default standard operating procedures or procedures provided by clients or sponsors as outlined in approved proposals . 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 . 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

0

0

Must have validated computerized systems that include the hardware and software for the intended use . 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 . 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 .



13.0 Change Control

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

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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 . 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 . Replacement in kind, or like for like change should not require the same level of review as change to different design specifications . 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)

0

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0

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



15.0 Complaints and Recalls

15.1 General (211.198)

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

0

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. 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

0

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 . 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 .



" 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

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 . 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

0

Bioanalytical studies for pharmaceuticals supporting clinical and pre-clinical trials should be executed in accordance with 21CFR58, GLP for pre-clinical trials . 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 .



0

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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 . 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") . 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 . 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 . 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) . 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



0

.

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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 . 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 . 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 .



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 .



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.



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.



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



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

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


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 .



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 .



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 . ,



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


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