enkap_quality_manual (1).pdf

GX P QUA LIT Y M A NUA L DR A F T DOCUMENT FOR COMMENT V ERSION 1.0

GXP Quality ManualDraft Document for Comment

Version 1.0

Presented for comment March 2009

© COPYRIGHT 2009 ENKAP

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c/o Glenn Melvin

Publisher

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We Welcome Your Comments!

Invitation to Contribute Your ExpertiseGXP Quality Manual

Draft Document for CommentVersion 1.0

enKap is pleased to offer you the opportunity to contribute your expertise by considering your comments related to the following areas of this draft document:

Accuracy Clarity Organization Adequacy of detail Additional subject areas Usability Industry References - Regulations, Guidelines, Standards, etc…

Incorporating comments into Version 2.0 of this document is our main objective. Our faculty of Subject Matter Experts (SMEs) will review all comments and suggestions for consideration in Version 2.0.

We look forward to your response.

Thank you for your consideration.

Glenn Melvin President enKap

Draft Document For Comment GXP Quality Manual

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Table of Contents

1. EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1

2. DEFINITIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2

3. MANAGEMENT RESPONSIBILITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3

4. QUALITY COUNCIL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4

5. QUALITY SYSTEM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5

6. CONTRACT REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7

7. DESIGN CONTROL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7

8. DOCUMENT CONTROL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9

9. PURCHASING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

10. PRODUCT IDENTIFICATION AND TRACEABILITY . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

11. PROCESS CONTROL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

12. INSPECTION AND TESTING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

13. CONTROL OF INSPECTION, MEASURING AND TEST EQUIPMENT . . . . . . . . . . . . 11

14. INSPECTION AND TEST STATUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

15. CONTROL OF NON-CONFORMING PRODUCT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

16. CORRECTIVE AND PREVENTATIVE ACTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

17. CONTROL OF QUALITY RECORDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

18. INTERNAL QUALITY AUDITING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

19. TRAINING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

20. RISK ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

21. STATISTICAL TECHNIQUES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14


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1. EXECUTIVE SUMMARY

Purpose

The world pharmaceutical market is increasingly competitive as more new products are launched and

governments continue to exert downwards pressure on healthcare costs. The ability to succeed in this

business environment depends, in part, on a company’s ability to supply products that consistently

satisfy customer expectations with respect to efficacy, safety, and quality, and to deliver them on time.

Achievement of this goal requires adherence to the highest standards of quality in all the activities

necessary to discover, develop, manufacture and supply products.

Principles of quality management have been adopted that ensure that employees and third-party

contractors routinely comply with the requirements of regulatory authorities, satisfy customer

expectations and minimize costs. These principles of quality management are based on the philosophy of

“correct the first time.”

This Quality Manual is intended as supplementary to other quality-based operating principles, and

provides an overview of the state of affairs, from a quality assurance department standpoint. The

established quality system and approach to quality serves as the cornerstone of current and future

success of the company. The company will be a cost effective and consistent supplier of pharmaceutical

products only when integrated quality principles and standards have been integrated in as part of daily

business activities.

This Quality Manual is a documented overview of the efficacy of the established quality system, and

serves as a conduit for the identification and ultimate implementation of continuous improvement

initiatives.

A Corporate Quality Policy has also been established, which is intended to serve as the framework for

continuous improvement within the organization, and to manage quality objectives with third-party GXP

subcontractors, as well as meet expectations for quality. The Quality Manual authorizes and governs the

creation of subsidiary quality-related documentation, as promulgated by Standard Operating Procedures

(SOPs), guidelines and policies as they relate to GXP operational areas throughout the organization. This

Quality Manual is based on general principles of ISO 9000 and 21 CFR 820, but also include exceptions

and additions where deemed appropriate, based on the requirements of quality for a GXP operating

environment. The requirements and quality standards addressed in this quality manual are intended to

meet the requirements of the regulations which govern good practice in the conduct of clinical studies,

non-clinical studies, and clinical and commercial manufacturing operations.

Scope

The Quality Manual applies to all company functions, duties, activities, and responsibilities, including the

use of third-party operations which perform GXP operational tasks that affect the quality of manufactured

pharmaceutical products, nonclinical studies and clinical studies sponsored by the company

Review and Control

The Quality Manual will be reviewed and re-issued annually to ensure that current operational quality-

based practices and processes remain aligned with set corporate business objectives and current

FDA requirements. An annual Quality Report will be issued as a controlled document, is considered

confidential, and must not be copied, re-printed or the contents divulged to third-parties without the

explicit written authorization of the Quality Assurance department.



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2. DEFINITIONS

Annual Quality Report - A report issued annually by the Quality Assurance department which presents the

results of progress on quality-based initiatives within the company, and identifies additional opportunities for

continuous improvement.

Contract Review - The systematic activities carried out before signing the contract to ensure that

requirements for quality are adequately defined, free of ambiguity, documented and feasible by the supplier

or service provider.

Corrective Action - An action taken to eliminate the causes of an existing non-conformity, defect, or other

undesirable situation to prevent recurrence.

Deviation - Written authorization prior to production or before provision of a service to depart from specified

requirements for a specified quantity or for a specified time.

Management Review - A formal quality evaluation by top management of the status and adequacy of the

quality system in relation to quality policy and new objectives resulting from changing circumstances.

Preventative Action - An action taken to eliminate the causes of a potential non-conformity, defect, or other

undesirable situation to prevent occurrence.

Quality - The totality of features and characteristics of a product or service that bear on its ability to satisfy

stated or implied needs.

Quality Assurance - All those planned and systematic actions to be implemented and demonstrated to

provide adequate confidence that an entity will satisfy given requirements for quality.

Quality Control - Operational techniques and activities that are used to fulfill requirements for quality.

Quality Management Review Committee (Quality Council) - A committee comprised of senior

management, including representatives from Research & Development, Commercial Operations, Quality

Assurance Department and Company President to conduct a formal quality evaluation of the status and

adequacy of the quality system. The Quality Council meets on an as needed basis, and all meeting minutes

from Quality Council meetings are retained in the Quality Assurance department.

Quality Management - All activities of the overall management function that determine the quality policy,

objectives, and responsibilities, and implement them by means, such as quality planning, quality control,

quality assurance and quality improvement.

Quality Manual - A document stating the quality policy and describing the quality system of an organization.

Quality Plan - A document which defines specific quality practices, resources, and sequence of activities

relevant to a particular product, project or contract.

Quality Policy - The overall quality intentions and direction of an organization related to quality, as formally

expressed by top management.

Quality System - The organizational structure, responsibilities, procedures, processes and resources for

implementing quality management.


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Quality System Review - A formal evaluation by top management of the status and adequacy of the quality

system in relation to quality policy and new objectives resulting from changing circumstances.

3. MANAGEMENT RESPONSIBILITY

Senior management is responsible for establishing the leadership role for ensuring quality performance and

providing the required resources to all operating units and departments to achieve these established quality

performance standards.

Management with executive responsibility shall ensure that the quality policy is understood, implemented,

and maintained at all levels of the organization. Senior management with executive responsibility, as defined

under the membership of the Quality Management Committee (Quality Council), will review the suitability and

effectiveness of the quality system on an annual basis, at a minimum, to ensure that the quality objectives

and requirements of the Quality System Manual are met. This review will include:

Identification of weaknesses and deficiencies in the Quality System, including those identified as a •

result of internal and external audits and investigations and consideration of possible improvement

Reporting of test data, customer complaints and resulting investigations to identify areas where •

nonconformities can be reduced or prevented

Verification that Corrective and Preventive Action (CAPA) procedures are effective•

Results of other quality improvement activities•

Management Engagement & Oversight

Responsibility for effectiveness of the Quality System includes participation by all employees, including

management. The company has provided all members of the organization with the knowledge that quality is

the responsibility of every employee. With respect to product, process, and the quality system, all members

of the organization are responsible for, and authorized to:

Take action to prevent the occurrence of non-conformities•

Identify and record problems•

Recommend and implement solutions•

All employees of the organization are authorized to propose changes to the quality system. This includes

changes to policies, guidelines, procedures and practices. The proposals are subject to specified reviews and

approvals. All members of the organization are strongly encouraged to suggest and implement improvement

ideas.

Research & Development Management and Commercial Operations Management

The Research & Development and Commercial Operations Management are responsible for:

Supporting quality objectives through the preparation, issuance, continuous review, revision, •

identification of areas for procedure(s) consolidation and eventual retirement of SOPs and related

guidelines

Ensuring that all required personnel are aware and trained in the requirements of the established •

Quality System, including SOPs and related guidelines

Ensuring that all third-party operations used for any or all of the conduct of clinical studies, non-clinical •

studies and manufacturing operations adhere to the requirements of the Quality System, contractual

requirements, SOPs and guidelines



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Quality Management

The Quality Assurance department has the responsibility and authority to ensure that the quality system is

maintained by:

Assuring the implementation of procedures that are required based on regulatory agency expectations •

and the Quality Manual

Ensuring that all required personnel are trained in the requirements of the Quality Manual, SOPs, •

guidelines and policies

Monitoring the performance of company operations and third-party operations to assure conformance •

to the requirements of the Quality Manual, as promulgated under established SOPs and working

practice guidelines

Overseeing the quality system and reporting regularly to management regarding any quality issues •

Reviewing contracts and assuring that the requirements for quality are planned and documented•

Analyzing and reporting on issues of product, process, service and system non-conformity, including •

customer complaints

Verifying the implementation of CAPA•

Ensuring adequate documentation is available for describing all aspects of the GXP compliance •

requirements

Implementing a system for conducting internal quality system audits and evaluation of third-party •

operations providing products or service

Coordinating training activities•

Conducting an annual review of the quality system and reporting the findings of that annual review in a •

Quality Annual Report

Quality Management, Research & Development Management and Commercial Operations Management –

Joint Responsibilities

Quality Management is required to be organizationally independent of Research & Development and

Commercial Operations Management. However, these functions may share responsibilities in areas, such as:

Authorization of written procedures•

Training•

Approval and monitoring of third-party operations•

Retention of records•

Monitoring of compliance to GXP requirements•

Investigation of quality problems•

4. QUALITY COUNCIL

Management review of the established Quality System historically was conducted within the Quality

Council. The Quality Council is defined as a committee of senior management comprised of Research &

Development, Commercial Operations, Quality Assurance and Company President. The Quality Council

meets on a periodic basis, to review opportunities for improvement to the quality management system,

including the Quality Manual, and review and discuss quality problems within the organization and third-party

operations, review trending results and metrics of quality incidents, and agree to required actions to minimize

recurrence and ensure continuous improvement. Meeting minutes from all previous Quality Council meetings

are required to be recorded and are maintained in the Quality Assurance department files.


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Resource Management

Each department is responsible for identifying resource needs, including GXP training requirements for

personnel, to ensure that personnel performing activities for which they have responsibility and authority,

have been trained accordingly. Management is responsible for providing adequate, qualified resources.

Training records are maintained by the Human Resources department.

Quality Policy

The quality policy is designed to promote a quality culture within the organization. The quality policy will

ensure that regulatory requirements and the perceived quality needs of customers are met during the

development, manufacture, testing, distribution of clinical and commercial products, and conduct of non-

clinical and clinical studies.

Quality is the key element in satisfying customer needs and expectations, in measuring company

performance. To achieve quality performance, a set of comprehensive quality standards have been

developed that will enable the company to meet or exceed governmental regulatory requirements.

The company strives to continuously improve its reputation for quality performance throughout its operations

and all activities. This is exhibited by the continuous training that employees receive in appropriate job skills,

GLP regulations, GCP regulations, and GMP regulations, procedures, guidelines and policies. In addition,

another attribute of the quality policy is a commitment towards continuous improvement in the evaluation of

projects and services, during and after execution for identifying opportunities for improvement.

Goals of the quality policy are met by the promotion and use of the quality systems, quality assessment tools,

and technologies designed to produce clinical and commercial products, design and execute non-clinical and

clinical studies that meet or exceed regulatory requirements, and meet business needs and development of

well-trained employees.

All employees have a responsibility for achieving these high quality expectations set forth in the Quality

Manual.

The company is committed to develop, manufacture and release safe, effective and high quality

pharmaceutical products that comply with applicable regulations and standards that meet identity, strength,

quality, purity, safety, stability and performance requirements. The company’s commitment to quality is an

integral and measured part of every aspect of our operation.

5. QUALITY SYSTEM

General

The Quality System has been established, documented and maintained as a means of ensuring that products

and services conform to specified requirements. The Quality Manual is a documented overview of the Quality

System and serves as a reference in the implementation and maintenance of that system.



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The Quality System serves as a platform for continuous improvement within the organization, and is

designed to address the needs of three (3) main customers, including compliance requirements from

regulatory agencies, quality expectations of patients and healthcare providers and company shareholders.

The structure of the documentation used to define the quality system includes four levels.


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The first level is the Quality Manual, which includes the Quality Policy.

The second level is the standard operating procedures, which define the detailed operational requirements of

the Quality System within the company.

The third level is the quality system procedural guidelines that support standard operating procedures.

The fourth level represents records and reports as documented evidence of compliance to established

written procedures.

Quality System Procedures

The company has documented and implemented procedures in accordance with the requirements of the

Quality Manual. The details of these procedures depend on the complexity of the work, as well as the skills

and training needed by personnel implementing the procedures.

Quality Planning

Requirements for quality are defined and documented in quality plans, internal and external audit plans,

product specifications, process and cleaning protocols, nonclinical study protocols, clinical protocols, case

report forms, quality agreements and contracts with service providers and suppliers. These documents are

reviewed before approval to ensure quality expectations will be satisfied.

6. CONTRACT REVIEW

Contracts are prepared and reviewed prior to final agreement with service providers and suppliers. A

potential subcontractor or supplier must submit appropriate background information relating to facilities,

equipment, capacity, dosage form requirements, regulatory inspection history and organizational structure to

enable an initial evaluation of their capability to undertake the work associated with the contract.

Contracts are prepared and reviewed prior to final agreement with the service provider or supplier. The

review assures that requirements are adequately defined and that appropriate capabilities will be available

to meet requirements. Where applicable, contracts are required to comply with 21 CFR 312.52: Transfer of

Obligations to a Contract Research Organization.

Amendments to contracts receive the same review process as original contracts. Any amendment is correctly

transferred to the responsible functional group(s). Contract review records are maintained in a designated

file. Under established procedures, contracts with third-parties also are required to include documentation

supporting the training, education and experience of the third-party provider personnel (21 CFR 211.34).

As required, a quality agreement may be established for critical Contract Research Organizations, vendors

and suppliers, in order to augment existing contractual arrangements which further define specific roles and

responsibilities for quality requirements between the company and third-party operations.

7. DESIGN CONTROL

Design control depends upon project scope, GXP functional area involved, and if a third-party operation

is used, the service provider or supplier contract requirements. Design reviews include the review of

clinical protocols, nonclinical protocols, and master batch production records, prior to execution. These

design reviews are conducted by functional area, as defined within the scope of SOPs, working practice

guidelines or policies, as well as the quality assurance department, to ensure quality is built into the study or

manufacturing process.

Procedures have been established and implemented to control and verify the design of contracts, quality



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agreements, protocols intended for non-clinical and clinical studies, master schedules for nonclinical studies,

master batch record review, development reports and process validation protocols. These documents are

reviewed to ensure that they are written in sufficient detail, so that scientific and compliance requirements are

met and serve as the plan for design and development activities. This includes identifying functional group

responsibilities and resources required for implementation.

The organizational interfaces between different functional groups involved in the design process includes

Research and Development; which includes Discovery, Toxicology (nonclinical safety assessment), Clinical,

Pharmacovigilance, Biometrics and Regulatory Affairs; and Corporate Operations which includes Contracts

Administration department, Project Management, Information Management, Information Technology,

Marketing, Finance, Human Resources, Manufacturing and Quality Assurance.

The design process includes significant information sought from and transmitted, in many cases, to third-

party operations. Information is documented in various forms, such as study reports, batch records,

controlled notebooks, trial master files, case report forms, product or study transfer reports, computer

printouts, medical information, contracts, quality agreements and study design requirements for intended

outcome. Design progress and issues are transmitted and reviewed within functional groups and third-party

operations based on project scope and contract requirements.

Design Input

Design inputs are identified in study objectives, product specifications and contracts with third-party

operations. These design inputs include molecular modeling, new compound screening models, market

research, formulations development, development reports, product specifications, method development and

manufacturing equipment cleaning verification studies.

Early animal screening and initial acute non-clinical study requirements are reviewed to ensure that quality is

built into the longer term chronic studies where compliance issues or scientific design of the study is critical

for the data to be submitted to regulatory agencies. Design input factors for nonclinical studies include

controls for personnel, control of test articles, animal care, facilities and equipment, study design, study

conduct, reporting of results, storage and retrieval of data.

Exploratory Phase I and Phase II clinical studies for determining safety profile and dose ranging requirements

are used to ensure the optimum design characteristics are included in later confirmatory Phase III clinical

trials. Review of Phase I and II clinical trial information allows determination of any significant systematic

flaws before initiating Phase III clinical trials. These system-related deficiencies can be corrected by protocol

design changes, case report form changes and enhancements in monitoring and training prior to initiation

of Phase III clinical trials. All studies and clinical trial product are designed to meet required regulatory

compliance requirements and standards, standard operating procedure, policy and working practice guideline

requirements.

Risk analysis is a required element of design input to identify issues related to safety of a new chemical entity

undergoing non-clinical assessment and Phase I safety clinical trials.

Design Output

Design output is documented in terms that can be verified or validated against design input requirements.

The output of these design activities are case report forms, master and executed batch records, study

protocols, process validation protocols and reports, cleaning validation protocols and reports, identification

of new compounds for clinical safety evaluation, and adequate, well-controlled and closely monitored safety,

exploratory and confirmatory clinical studies. These documents are developed to meet the design input

requirements, and reference acceptance criteria and other information crucial to the process or product

design.


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Design Reviews

Periodic planned and documented reviews of the designed process are performed by representatives of the

responsible functional groups involved in the design stage. As required, an independent person is involved

in conducting a review of the design input and resulting output. This review can be performed by a qualified

third-party consultant. Formal documented reviews of the design include, but are not limited to, the conduct of

interim analysis of exploratory clinical studies, the contract review process for third-party operations involved

in performing portions or all of the work, as well as clinical study reports, executed batch records and product

release certificate of analysis, method validation reports, process validation reports, cleaning validation

reports and nonclinical draft and final reports. These reports require approval from the functional groups, as

defined in applicable SOPs.

Design Verification

As the design process proceeds, design verification is conducted and documented to ensure that design

output corresponds to design input, i.e., product specifications met, or clinical study protocol requirements

satisfied. Verification that design inputs meet design outputs is accomplished by design reviews. Executed

batch records are reviewed against master batch record requirements; clinical batch manufacture, stability

batch manufacture and production batches are verified as meeting requirements, by subjecting the developed

product to in-process testing, final release testing and stability testing requirements, and if deemed

acceptable, the issuance of a GMP Certificate of Compliance. Nonclinical and clinical studies are verified

as meeting design input requirements by Quality Assurance oversight by the issuance of a GLP Compliance

Statement and issuance of a GCP Audit Certificate, respectively. Analytical methodology development,

product specification development based on process capability, and completion of adequate and well-

controlled pivotal Phase III clinical trials are examples of design verification.

Design Transfer

SOPs and related control documentation are used to ensure that non-clinical studies, clinical laboratory

methodology, bio-analytical methods, manufacturing process and quality control analytical methodology

transfers are approved and meet contractual and regulatory compliance requirements.

Design and Process Changes

Changes to designs are documented by change control procedures, note to file, or under revision logs or

amendments to control records, such as SOPs, clinical study protocols, non-clinical study protocols, product

monographs, analytical methods or batch records. Design changes are implemented as product or process

continuous improvements based on design reviews, risk analysis, customer complaints, or CAPA resulting

from quality investigations and audits.

8. DOCUMENT CONTROL

Written procedures continue to be used to control and maintain documentation. The magnitude of control

is dependent on the type of document. Procedures have been established and are maintained to control

all Quality System documentation. These procedures describe the requirements for development, review,

approval, maintenance and retirement of SOPs, working practice guidelines and policies. All documentation

is uniquely identified. Documents are reviewed and approved by authorized personnel prior to issue. SOPs

are reviewed and updated as necessary, and on a default biennial basis. Documents are reviewed for the

purpose of re-issue after changes have been made, or in some cases, as part of the retirement phase of

the controlled document. Information of the description of the change, reason for the change, and in some

cases, the impact of the change, is required to be included. Superseded document masters are retained and

archived according to record retention procedures.



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9. PURCHASING

Documented procedures are used to control and coordinate purchasing activities. Third-party operations who

conduct non-clinical, clinical and manufacturing services are responsible to source qualified materials and

services. Suppliers are initially approved by evaluation of their capability. Procedures are in place to ensure

third-party operations are evaluated for business, quality and regulatory requirements. Third-party operations

are evaluated and selected on the basis of their ability to meet sub-contracted activity requirements. The

extent of control exercised over third-party operations depends on the impact of the sub-contracted service

on the product or process and previously demonstrated capability and performance. Records are maintained

of vendor audits and performance. All critical approved suppliers and service providers are required to accept

and sign a contractual agreement that defines basic quality and regulatory issues, including right to audit,

notification of change to the customer and regulatory inspection notification.

Purchase orders are required to contain data clearly defining the product or service being requested,

including precise identification by code, and/or specification providing the title and specified requirements.

Dependent on the type of service or supplier, quality assurance will review and approve purchasing

documents for adequacy of the specified requirements or performance standard prior to release. Copies of all

purchasing documents are retained.

Verification of Purchased Product

Purchased product or services will be verified to assure contract obligations have been met. In some

cases, the product or service will be evaluated at the supplier or service provider site by periodic quality

assessments.

10. PRODUCT IDENTIFICATION AND TRACEABILITY

At third-party operations, documented procedures have been established and are implemented for identifying

materials from receipt to final product release and shipment or executed protocols, case report forms or

final study reports. All finished product is identified by a unique reference number. Products intended for

use in company sponsored studies or as marketed product, are released by the company as the study

sponsor, and assigned a unique quality disposition release number. Traceability records include purchase

orders, certificates of analysis, certificates of compliance, process control charts, records of environmental

conditions and shipping records. Clinical packaging third-party operations and distribution centers for

marketed products are required to maintain records of the manufacture and distribution of clinical supplies

and commercially distributed product, respectively.

11. PROCESS CONTROL

Third-party operations used by the company have procedures that ensure non-clinical or clinical protocol

execution or material production is planned and carried out under controlled conditions in order to prevent

nonconformities. Critical process parameters are required to be identified and controlled to ensure

performance specifications are met. Controlled conditions include the following:

Batch records to define production requirements that are established and implemented to assure that •

products have the safety, identity, strength, quality and purity they are purported to have.

Production equipment is approved based on installation and operation qualification requirements.•

Qualified personnel are used for process execution•

Facilities are designed and have adequate capacity to ensure segregation of materials, study subjects •

and animal cages, to minimize mix-ups and cross-contamination

Processes are controlled through a variety of approaches, activities and techniques. The process control


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system is designed to control information, material and operator input into the process; technology, tools and

equipment used, process environment, process performance and process output.

Process controls used in clinical studies include the use of clinical monitoring, protocol stopping rules and

requirements for determining and adequately recording endpoint safety and efficacy information. The control

and verification of source documentation are critical process parameters in the conduct of adequate and well-

controlled clinical trials. The sampling and control of bio-samples at critical time points also comprise process

control during clinical studies. Criteria for in-process evaluation, recording of critical system outputs and final

testing are also required for process control. Equipment and utilities that are used during material production

or study protocol execution are required to have suitable documented procedures for set-up, cleaning,

qualification calibration and preventative maintenance. Where the results of processes cannot be fully verified

by subsequent inspection, processes are carried out by qualified operators and require control of collection

of process parameters to ensure specified requirements are met. Processes are qualified as required by

specified requirements and regulatory requirements.

Records of process and equipment qualification, and descriptions of clinical and non-clinical study areas are

maintained as specified by specific procedures. Monitoring and control of process parameters and in-process

and finished product or study characteristics are performed and recorded in batch records, clinical and non-

clinical protocols and reports.

12. INSPECTION AND TESTING

Inspection and testing activities, including specified requirements and resulting records, are documented

in SOPs, working practice guidelines, policies, laboratory notebooks, batch records, case report forms,

monographs, protocols, clinical study reports and draft and final non-clinical study reports. Documented

procedures are used to control and coordinate this activity supported by quality records.

Inputs to creating inspection requirements include contract requirements, batch record and protocol

requirements. Inspections are carried out with prescribed documents using qualified equipment and trained

personnel. Inspections may be performed by quality control personnel, study directors, study monitors,

clinical monitors or quality assurance personnel. Deviations, variances, exceptions and Out-Of-Specification

(OOS) test results are investigated, root cause identified and used in justifying final inspection, testing results

and product or study disposition.

Inspection and testing records are documented on certificate of analysis, executed protocols and site

monitoring trip reports. Records, including the identity of the person(s) performing the inspection or testing,

are maintained on file.

13. CONTROL OF INSPECTION, MEASURING AND TEST EQUIPMENT

All inspection, measuring and test equipment used at third-party operations have suitable procedures for set-

up, operation, cleaning, qualification, calibration and preventative maintenance. Test equipment is qualified

by documented procedures. Test methods used for product testing, clinical sample analysis and non-clinical

sample analysis are validated in accordance with documented procedures, and ensure that the measurement

uncertainty is known and consistent with the required measurement capability. This also includes the

checking and periodic re-checking of test software.

All equipment used for inspection, measuring and testing is uniquely identified, including traceability to

equipment model, location and calibration and preventative maintenance frequency requirements. Inspection,

measuring and test equipment and methods are selected to satisfy precision and accuracy requirements.

Records of calibration status, methodology used and test results are maintained according to documented

procedures. When equipment is determined to be out- of-calibration, the validity of the previous test results



12 www.enKap.com

using the identified out-of-calibration equipment are required to be investigated and reconciled.

14. INSPECTION AND TEST STATUS

Third-party operations inspection and test status of product is identified to ensure that only product that

has passed the required inspections and undergoes quality disposition as approved is used for intended

investigative studies or distributed as commercial product. All products are identified to indicate conformance

or non-conformance with regard to inspection and test results. Only product that has passed the required

inspections and tests are permitted for release. Only clinical study reports, and final study reports from non-

clinical studies that have undergone final quality control and quality assurance inspection are considered

approved. After inspection and test status by the third-party operation, the final authority responsible for the

release and disposition of conforming product or study is the Quality Assurance department.

15. CONTROL OF NON-CONFORMING PRODUCT

Product that does not conform to requirements specified in product acceptance criteria, protocols and

batch records are prevented from unintended use. Documented procedures are used to describe how

nonconforming products are identified, documented, evaluated, segregated, dispositioned and notification

provided from third-party operations to the company. Investigations to identify root cause and subsequent

actions are performed using documented procedures. Investigations of non-conformances are documented

on investigation forms and approved by Quality Assurance. Each nonconforming product investigation report

is uniquely identified.

The responsibility for review of nonconforming product ultimately rests with the Quality Assurance

department. Quality Assurance has the authority for dispositioning nonconforming product. Documented

procedures are used to investigate and determine subsequent actions.

Disposition alternatives include:

Rework or reprocess in accordance with documented procedures and regulatory requirements. •

Rework and reprocessed product is treated and tested identically to the product with additional testing

performed, including stability testing, as required to maintain control of the product and demonstrate

equivalence to normally processed product

Reject and potential use for equipment or process qualification activities•

16. CORRECTIVE AND PREVENTATIVE ACTION

Documented procedures for conducting investigations and identifying CAPA are established and maintained.

Any CAPA is commensurate with the risks involved and the magnitude of the problem.

Procedures for corrective action include effective handling and investigation of product and process

nonconformities, serious adverse events, customer complaints, Quality System nonconformities and

deviations and exceptions to non-clinical and clinical studies. Documented procedures are used to conduct

investigations to determine if the root cause is process-related, personnel-related or equipment-related.

Corrective action plans are then developed, implemented and their effectiveness evaluated.

Procedures for preventative action are established to minimize occurrence of nonconformities. These

procedures produce information that is analyzed to detect and eliminate potential, as well as actual, causes

of nonconformities. This information includes audit results, inspection and test results and management

reviews.

Preventative action plans serve as the basis for continuous improvement within the organization.


www.enKap.com 13


Customer complaints are classified into categories to allow for better tracking of trends and evaluating

improvement in specific areas. Every complaint is communicated to relevant functions within the organization.

Responses to customer complaints are developed by the responsible functional group and reviewed by the

Quality Assurance department CAPA is implemented and verified as effective.

Relevant information regarding problems, including details of actions taken, are submitted as part of the

management review process, and are included, for commercially distributed product, as part of the annual

product reviews.

Records of CAPA are tracked and trended, and also maintained within investigation reports, deviation and

exception reports, quality incident reports and memos to files.

CAPA related to safety and performance of the product is reviewed by the Regulatory Affairs department to

determine whether they involve any incidents that meet regulatory reporting criteria.

17. CONTROL OF QUALITY RECORDS

Procedures have been established and implemented for the identification, collection, indexing, access,

filing, storage, maintenance and disposition of quality records in the Information (Records) Management

department. These requirements are designed to allow records to be legible and retrievable, and prevent

damage and deterioration. These records are essential for accurately demonstrating conformance to

specified requirements and effective operation of the quality system.

18. INTERNAL QUALITY AUDITING

Documented procedures have been established and implemented for performing internal quality audits. The

audits verify whether quality activities and related results comply with planned arrangements. The audits

are planned and scheduled by the Quality Assurance department based on importance of the activity to be

audited. Audits are performed by individuals whose primary responsibilities are independent of the activities

being audited. Results of audits are recorded in audit reports or in investigation report forms, where there

is a directed internal audit conducted as a requirement of an investigation or verification of CAPA. Quality

Assurance is required to follow up, verify and record implementation and effectiveness of corrective action(s)

taken. Results of quality audits are used as an input to the management review process.

19. TRAINING

Documented procedures for identifying training needs, including training in specific job skills, procedure

training and continuous training in regulatory requirements have been established. Personnel who perform

assigned tasks within the operation are required to be qualified on the basis of education, training and/or

experience.

Personnel qualification files are maintained for each employee, and include at a minimum, a written and

approved job description, curriculum vitae, records of training attended and procedures reviewed.

20. RISK ASSESSMENT

The intent of a well-designed quality system is to ideally prevent, if not minimize, re-occurrence of

deficiencies in order to meet regulatory requirements. The objective is to mitigate risk by process design

intended to eliminate risk. The end user of a well-designed pharmaceutical-based quality system is the

patient and consumer.



14 www.enKap.com

Risk management within the GXP operational areas include:

GLP: long-term non-clinical studies where protocol deviations, study design problems, contamination •

issues requiring frequent quality surveillance to ensure problems are identified early and appropriate

corrective action implemented.

GCP: (1) selection of qualified principal investigators and clinical sites suitable to comply with protocol •

defined study requirements, (2) conceiving well-designed studies that minimize protocol exceptions/

deviations/violations and (3) introduction of qualified personnel to implement processes grounded in

compliance, efficiency, and ethical foundations.

GMP: quality surveillance and manufacturing personnel present at the Contract Manufacturing •

Organization (CMO) during critical process steps, such as process validation runs and cleaning

validation, as well as technology transfer from one CMO to another CMO.

21. STATISTICAL TECHNIQUES

Statistical techniques are used for a variety of activities, including inspection sampling at third-party

operations, process and method validation, process capability, environmental monitoring, and statistical

analysis plans used in the interpretation of executed clinical protocols and quality improvements.

Procedures have been established and implemented to define and control the application of statistical

technique. These include use of process capability calculations to ensure an established validated

manufacturing process routinely operates within defined specifications relative to process variability.


Conducting Effective !

Computer Validations: Effective Documentation Requirements

Software Validation !

Defining User Requirement !

Specifications

SAP Validation !

Excel Spreadsheets: !

Validated Use in a Regulatory Environment

Electronic Records !

Management

Risk Analysis !

Interpreting FDA !

Regulations

Data Integrity !

ERP Validation !

Configuration Management/ !

Change Control

Qualifying Vendors/Vendor !

Requirements

Validation of Configurable !

Off-The-Shelf (COTS) Computer Systems

Preparing For/Managing an !

FDA inspection

LIMS !

Validation of PLC Systems !

Network Qualification !

Equipment Qualification !

Validation and Use of MS !

Access Databases

Writing Effective Test !

Scripts

There are a number of benefits of being one of our published authors:

Establishes Yourself as an Industry Expert. By demonstrating your expertise, you move into a select group; setting yourself apart from non published colleagues.

Industry Best Practice. You are playing a role in helping advance the current state of industry best practice. You are making a difference.

Builds Credibility and Name Recognition. Consulting and speaking opportunities may present themselves in the future.

Tests Your Expertise Against our Peer-Review Process. How do you measure up? Can you produce excellence?

Giving Back. You are sharing your ideas with fellow industry professionals.

Great Addition. In the event of a job search, a great addition to your resume.

CALL FOR AUTHORS

TOPICS TO CHOOSE TO WRITE ON INCLUDE THE FOLLOWING:

System Level Impact !

Assessment for Computer Systems and Software Packages

Validation of CAPA !

Effectiveness

Computerized Laboratory !

Systems

Validation and Part 11 !

Compliance of Electronic Document Management Systems

IQ, OQ and PQ !

Internal/Supplier Auditing !

Maintaining Computer !

Systems in a Validated State

Industry Best Practice !

Retirement of Computer !

Systems

Software Lifecycle !

Development Cycle (SDLC)

Validation vs. Qualification !

Disaster Recovery Planning !

Warning Letters !

Master Planning !

Computer Systems !

Evaluations

Validation in a Virtual !

Environment

Custom Application !

Validation

Revalidation !

Computerized Systems for !

GCP, GLP

Training !

For more information, please contact Glenn Melvin, Publisher at 561-795-2785 or

glenn!enkap.com

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