SOP 08-IPEA Certification Criteria Rev 2

STANDARD OPERATING PROCEDURE
International Pharmaceutical Excipients Auditing, Inc.

Title Revision SOP Number
Certification Criteria
Originator Approved By
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Effective Date Page
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Irwin Silverstein
IPEA Management Committee
Feb. 17, 2011
PURPOSE: This document establishes expectations and criteria for substantial conformance to the Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients. SCOPE: These criteria are applicable to excipients for which certification is sought. RESPONSIBILITIES: 1. Certification Board Member: Board members objectively review the Certification Audit Report to establish substantial conformance to excipient GMP requirements. 2. Lead Auditor: Audit team member with responsibility for the conduct of the audit including issuing the draft report whose contents are in conformance with SOP 24. 3. Report Reviewer: Assures the audit report conforms to SOP 24 and that ratings in the report as recommended by the auditor are appropriate according to Appendix A of this SOP. REFERENCES: 1. The Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients, 2006 2. The Joint IPEC-PQG Good Manufacturing Practices Audit Guide for Pharmaceutical Excipients, 2007 3. ISO 9001:2000 Quality Management Systems. Fundamentals and vocabulary 4. ISO 9001:2008 Quality Management Systems. Requirements 5. IPEC-AMERICAS Significant Change Guide 2005 6. IPEC-AMERICAS Certificate of Analysis Guide for Bulk Pharmaceutical Excipients 2000 7. SOP 9, Certificate of Excipient GMP Conformance 8. SOP 16, Appeals, Complaints, and Disputes 9. SOP 19, Quality System Change Notification 10. SOP 20, Conducting the Certification Audit 11. SOP 24, Documenting the Certification Audit DEFINITIONS: 1. See Glossary PROCEDURE: 1. The Lead Auditor assures Qualified Auditors perform an assessment of the excipient site of manufacture following SOP 20 and issues a report in accordance with SOP 24. 2. The Lead Auditor, in conjunction with members of the Audit Team, assigns a rating to each section of the audit report using Appendix A of this SOP as a guide.

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Irwin Silverstein
Feb. 17, 2011
3.
4.
5.
6.
7.
The ratings are entered into the IPEA Certification Audit Report (SOP 24 Appendix B), indicating N/A where the section is not applicable. The Lead Auditor has the report reviewed by other team members and once all issues have been addressed, forwards the draft audit report to the IPEA office for Quality review. IPEA Executive Management assigns a Report Reviewer and the audit report is reviewed by the Report Reviewer for deviations from expectations as noted in SOP 24 for conducting and documenting the Certification Audit. Discrepancies are reconciled with the Lead Auditor. The Report Reviewer sends the updated Certification Audit Report to the IPEA Administrator. The IPEA Administrator then submits the audit report to the applicant site representative for review and comment. The Report Reviewer discusses comments from the applicant with the Lead Auditor. The applicant is notified of any disagreement and can dispute or appeal the matter (SOP 16). IPEA Executive Management is notified that the site assessment and conformance evaluation have been completed. IPEA Executive Management assigns members to the Certification Board and schedules a meeting. Each Board member will receive a copy of the certification application, audit report, and other relevant information for their review at least one week prior to the meeting. The auditor(s) who conducted the audit attends the meeting to answer questions from the Certification Board. For all findings of Does Not Meet or Partially Meets the applicant is required to provide a corrective action plan that satisfactorily addresses the issues or provide a written explanation of why they feel no action is needed. The plan or explanation is reviewed by the audit team to determine if it supports a recommendation for Certification to the Certification Board. a. If the Audit Team does not agree that the corrective action plan remediates one or more findings, the Applicant can modify the plan or ask that it be forwarded to the Certification Board as is without a recommendation from the audit team to certify. b. In addition, the Applicant may submit a corrective action plan for findings noted in the report as Substantially Meets (this is not required, but recommended) The Board members review the audit report, corrective action plan, and other relevant information to determine if the site substantially conforms to excipient GMP expectations. a. To be certified, the ratings in the Certification Audit Report for the site should meet the following expectations: i. There are no items rated as Critical Failure (CF). ii. There are no items rated as Does Not Meet (DM) unless the deficiency has been remediated or an interim control is in-place. iii. No section has enough items rated as Partially Meets (PM) to cumulatively indicate the Quality System is not effectively

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developed or implemented or that the practices or conditions lead to confirmed or highly probable adulteration of product, or significant deficiencies in required regulatory programs, likely to result in product recall or facility closure; and deficiencies likely would have gone undetected in the absence of the audit. iv. The audit report does not convey an impression that there is a significant risk that the quality system is not adequately established to assure the safety and quality of the excipient. b. The Board members vote as to whether or not the site is in an adequate state of conformance to excipient GMPs. Approval to grant certification requires a majority of the Board members present at the meeting. 8. The Board, at their discretion, may decide that items rated DM or PM must be remediated as described in the site corrective action plan prior to certifying the Applicant. Executive Management will inform the Applicant as to the expectations established by the Board. 9. Where the Board has recommended against certification, the applicant is advised of the nature of the deficiencies that should be corrected prior to their reapplication (see SOP 9, step 9b). a. The description of the deficiencies provided to the applicant should be such that they are actionable by the excipient manufacturer. IPEA Executive Management determines how to confirm corrective measures have been implemented. Upon implementation by the applicant, confirmation of the improvement is provided to the Certification Board along with the original audit report so that they may determine if the site is now in an adequate state of conformance to be certified. 10. The applicant is provided an opportunity to appeal the decision of the Certification Board as stipulated in SOP 16. 11. The auditable standard is based upon the current Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients as issued by IPECAmericas (www.ipecamericas.org). Revision of the IPEC-PQG Guide leads to revision of the auditable standard and the Certification Criteria and thus this procedure. Upon approval of the revised procedure, all certified applicants are notified of the changes in accordance with SOP 19.. 12. IPEA issues the Certification to Excipient GMP, within the scope of the application, when the manufacturer is in substantial conformance to the Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients. HISTORY OF REVISONS Description of Changes New Procedure Change reference from SOP 5 to SOP 24, provided for the applicant to review the draft report, and clarified the implementation of
Revision No. 0 1
Effective Date Dec 15, 2008 Aug. 28, 2009

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Irwin Silverstein
Feb. 17, 2011
Feb. 17, 2011
Certification Criteria is per SOP 19. Delete reference to Excipient GMP Conformance Assessment Table and insert requirement for corrective action plan for findings of DM or PM.
APPENDIX A
JOINT IPEC PQG GOOD MANUFACTURING PRACTICE (GMP) GUIDE FOR PHARMACEUTICAL EXCIPIENTS 2006
This document includes the Joint IPEC-PQG Manufacturing Practice Guide for Pharmaceutical Excipients 2006 and the corresponding Audit Checklist from the Audit Guide. Included in the audit checklist are descriptions of expected observations used to determine conformance with the guide. There are six Auditor Judgments used for summarizing the various Sections to the checklist: Fully Meets (FM) Evidence indicates system is effective. An effective, well-developed and executed Quality System. All checklist criteria for the section have been addressed, as applicable to this facilitys programs. Procedures are established, maintained and documented where so noted in the checklist, and can be corroborated by multiple parties and verified by objective evidence. Most of the Evidence indicates a good, functional Quality elements System is in place. However, established by the 1) a few applicable, minor audit checklist GMP Audit elements are not followed, Checklist were in 2) minor inconsistencies exist between place. (Almost implementation versus documented procedure, Fully Meets) 3) minor examples are evident of flawed record keeping, and / or 4) informal practices cannot be corroborated by multiple parties or objective evidence. (The term "minor" as used in this definition means that the observation is one that, if left uncorrected, could not adversely impact product quality, safety or security.) Most of the Evidence indicates a semi-functional Quality elements System is in place. However, established by the 1) most applicable, minor audit checklist elements GMP Audit are not followed in that section, Checklist were not 2) implementation has little resemblance to in place (Almost a documented procedure, and / or Does Not Meet) 3) recordkeeping is misleading, inaccurate or nonexistent. (The term "minor" as used in this definition means that the observation is one that, if left uncorrected, could not adversely impact product quality, safety or security.) Meets or exceeds the intent of the checklist in design and execution.
SOP 8
Substantially Meets (SM)
Partially Meets (PM)
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APPENDIX A Does Not Meet (DM) Key system elements of checklist missing and / or poorly designed and / or poorly executed. Critical Failure Clear evidence or (CF) direct observation that adulterated product might be released and / or a clear regulatory failure. Not Applicable A system that is or Not not needed or Auditable major portions are (NA) not controlled at this facility. Evidence indicates Quality System is not effectively developed or implemented. System is poorly designed or not followed. Multiple applicable checklist criteria for the section are missing or not performed. Multiple or repetitive deviations observed in execution or key records. Critical violation of GMPs with practices or conditions leading to confirmed or highly probable adulteration of product, or significant deficiencies in required regulatory programs, likely to result in product recall or facility closure; and deficiencies likely would have gone undetected in the absence of the audit. Systems described in this section are not needed because of the nature of products or processes at this facility, or systems are controlled somewhere other than by the facility, e.g., corporate, and there is insufficient direct evidence for the auditor to verify actual practices of the key criteria in the section or judge their consistency or effectiveness.
Joint IPEC-PQG Manufacturing Practice Guide for Pharmaceutical Excipients 2006 1 INTRODUCTION
1.1 Purpose and Scope This document is an internationally accepted Guide that defines the extent and point of application of appropriate Good Manufacturing Practice (GMP) principles for excipient manufacture. The Guide is applicable to the manufacture of excipients intended for use in drug products. It covers the quality management system and the extent of GMP necessary throughout manufacturing for both batch and continuous processes. It will assist both auditors and manufacturers to establish whether the facilities and controls used for the manufacture of excipients are adequate and whether the excipients possess the quality and purity which they purport to possess and are suitable for their intended use. The manufacture of certain excipients for specialist applications presents additional challenges that are outside of the scope of this Guide. Examples include excipients; for parenteral, ocular, inhalation, open wound use, that are sterile and/or pyrogen free, In these cases, it is recommended that guidelines and compliance programmes that provide detailed guidance for the manufacture of the related drug products can be consulted and adapted as necessary to the excipient in question. The Guide does not address the specific GMP relating to Good Trade and Distribution Practices (GTDP). For additional guidance on GMP for distributors refer to the WHO Good trade and distribution practices for pharmaceutical starting materials (see also Appendix C).
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APPENDIX A
1.2 Principles Adopted 1.2.1 The Guide and its Use Pharmaceutical excipients are diverse and often have uses other than for pharmaceutical applications. Each manufacturer should consider how this Guide might apply to their products and processes (for example batch versus continuous processes). Since excipients are so diverse, some principles of this Guide may not be applicable to certain products and manufacturing processes. For the purposes of this Guide the terms GMP and current Good Manufacturing Practice (cGMP) are equivalent. The term should indicates recommendations that are expected to apply unless shown to be inapplicable or replaced by an alternative that provides at least an equivalent level of quality assurance. Note that should does not mean must or shall. 1.2.2 Application The text provides the guidance necessary for the manufacture of excipients but not all of the details. As an international guidance document, it cannot specify national legal requirements or cover particular characteristics of every excipient. Quality System Standard The quality management system standard chosen as a framework for this Guide is ISO 9001, which is appropriate for manufacturing facilities. A manufacturer may apply the ISO standard with or without certification. But this is a business decision and not a recommendation of this Guide. However, ISO certification has the benefit of providing assurance to customers that the excipient manufacturers quality management system has been independently verified. The headings in this document have been aligned with the ISO 9001 clause numbers because many excipient manufacturers already use that standard as a basis for their quality management system. Additional headings are included as required to introduce the additional guidance on GMP when not covered by current ISO 9001 clauses. IPEC and the PQG believe that merging GMP principles for pharmaceutical excipient manufacturing into the ISO 9001 quality management system enhances not only quality management but also an organizations operational procedures. 1.3 Document Structure This Guide combines the concepts of existing GMP principles from the WHO (World Health Organization) GMP guidelines for excipients, the IPEC Good Manufacturing Practices Guide for Bulk Pharmaceutical Excipients 2001, IQA PQG PS 9100:2002 Pharmaceutical Excipients and international quality management system requirements as developed by the International Organization for Standardization (ISO). In view of the increasing globalisation of the pharmaceutical industry and the harmonisation of pharmaceutical registration requirements, relevant portions of the manufacturing concepts detailed in these schemes are employed throughout this Guide.
1.2.3
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SOP 8
APPENDIX A
Section 3 General Guidance provides an overview of the GMP criteria applicable to excipient manufacture and the point of application of excipient GMP. Sections 4 to 8 give guidance on the GMP principles and implementation of a quality management system suitable for excipient manufacture. For example these sections recommend measures to limit excipient contamination. No attempt has been made to include details specific to particular excipients. Individual manufacturers should address these as they apply to their own products and processes. The Appendices cover supporting guidance for excipient GMP including Auditing Considerations (which describes key criteria to be considered when auditing an excipient manufacturing facility), along with Definitions, Glossary and Bibliography.
2 DEFINITIONS
(SEE Joint IPEC-PQG Manufacturing Practice Guide for Pharmaceutical Excipients 2006 APPENDIX B)
3 GENERAL GUIDANCE
International regulations governing drugs require that they be produced, processed, packed and stored in accordance with GMP. Unlike pharmaceutical products and APIs, there was previously little guidance that specifically addresses the manufacture of pharmaceutical excipients. 3.1 Pharmaceutical Excipients Pharmaceutical excipients are substances other than the API, which have been appropriately evaluated for safety and are intentionally included in a drug delivery system. For example excipients can: aid in the processing of the drug delivery system during its manufacture, protect, support or enhance stability, bioavailability or patient acceptability, assist in product identification, enhance any other attribute of the overall safety, effectiveness or delivery of the drug during storage or use. 3.2 Excipient GMP Implementation The application of GMP is relevant once it has been determined that a chemical is intended for use as a component of a drug product. Excipient manufacture should be carried out in accordance with the GMP concepts consistent with this Guide. The objective of excipient GMP is to ensure that the manufacture of an excipient results in a consistent material with the desired quality characteristics. The emphasis of GMP for excipients is to assure product integrity, avoid product contamination and ensure that records are maintained. As the excipient manufacturing process progresses the degree of assurance concerning the quality of the product should increase. Manufacturing processes should be controlled and documented. However, at some logical processing step, as determined by the manufacturer, the GMP as described in this Guide should be applied and maintained.
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APPENDIX A
Judgement based on risk analysis and a thorough knowledge of the process is required to determine from which processing step GMP should be implemented. This is usually well before the final finishing operation and for example may be identified using methods such as HACCP (Hazard Analysis and Critical Control Point), FMEA (Failure Mode and Effects Analysis) or a detailed process flow diagram. Consideration should also be given to other factors such as batch versus continuous processing, dedicated versus multipurpose equipment, open versus closed processes. (see also Appendix A for further examples).
4 QUALITY MANAGEMENT SYSTEM- EXCIPIENT QUALITY SYSTEMS

4.1 General Requirements The principles outlined in this Guide provide a comprehensive basis for the quality management system used in the manufacture of pharmaceutical excipients. Excipient manufacturers should identify the quality management processes required to assure excipient quality. Where manufacturing, testing or other operations that could affect excipient quality are outsourced the responsibility for quality remains with the excipient manufacturer and control measures should be defined (see also 7.4.2) 4.2 Documentation Requirements 4.2.1 General The excipient manufacturer should have a system in place to control documents and data that relates to the requirements of the quality management system. Quality Manual The excipient manufacturer should prepare a quality manual describing the quality management system, the quality policy and the commitment of the excipient manufacturer to applying the appropriate GMP and quality management standards contained in this Guide. This manual should include the scope of the quality management system, reference to supporting procedures and a description of the interaction between quality management processes. Control of Documents The excipient manufacturer should establish and maintain procedures for the identification, collection, indexing, filing, storage, maintenance and disposition of controlled documents, including documents of external origin that are part of the quality management system. Procedures used in the manufacture of excipients should be documented, implemented and maintained. In addition, there should be formal controls relating to procedure approval, revision and distribution. These controls should provide assurance that the current version of a procedure is being used throughout the operational areas and previous revisions of documents have been removed. Documents and subsequent changes to documents should be reviewed and approved by designated qualified personnel before issuance to the appropriate
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4.2.2
4.2.3
APPENDIX A
areas, as identified in the documents. Documents that impact product quality should be reviewed and approved by the quality unit (see also 5.5.1). Controlled documents may include a unique identifier, date of issue and revision number to facilitate identification of the most recent document. The department with the responsibility for issuing the documents should be identified. Where practical, changes and the reasons for the change should be documented. Electronic documentation should meet the requirements for the document control system stated above. If electronic signatures are used on documents, they should be controlled to provide equivalent security to that given by a hand written signature. Electronic documents and signatures may also need to satisfy local regulatory requirements. 4.2.4 Control of Records The excipient manufacturer should establish and maintain procedures for the identification, collection, indexing, filing, storage, maintenance and disposition of records. Records should be maintained to demonstrate achievement of the required quality and the effective operation of the quality management system. Records should be legible and identifiable with the product involved. Pertinent subcontractor quality data should be an element of these records. Entries in records should be clear, indelible, made directly after performing the activity (in the order performed), signed and dated by the person making the entry. Corrections to entries should be signed and dated, leaving the original entry legible. Records should be kept for a defined period. This period should be appropriate to the excipient, its expiry date or re-evaluation interval. Records should be stored and maintained in such a manner that they are readily retrievable, in facilities that provide a suitable environment to minimise deterioration or damage. GMP Section Audited Item 4.2 Documentation Requirements 4.2.1 General 4.2.2 Quality Manual 1. Quality Manual Rating Expected Observation
4 QUALITY MANAGEMENT SYSTEMS-EXCIPIENT QUALITY SYSTEMS
2. Quality Policy 3. GMP starting point 4.2.3 Control of Documents 1. Written manufacturing instructions
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1. Manual is available and reviewed on schedule it describes the quality system and interaction between quality and management processes 2. Policy is deployed 3. Documentation supporting starting point for GMP available (see section 3.2) 1. Document control procedure in place. Documents available and in use
SOP 8
APPENDIX A
2. Process fully described 3. Verification of significant steps 4. SOP availability and control 2. Includes all appropriate instructions 3. Verify conformance to process 4. Only current documents are available to operators. Documents impacting quality approved by the quality unit. 5. Scheduled review verified 6. Prevent unauthorized change or approval 1. Written retention policy including storage and policy followed 2. Legible; signed, and dated in ink; errors properly corrected
5. Periodic review of SOPs 6. Electronic control 4.2.4 Control of Records 1. Record retention SOP 2. Good Documentation Practices
4.3 Change Control The excipient manufacturer should establish and maintain procedures to evaluate and approve changes that may have an impact on the quality of the excipient. For example this may include changes to: raw materials or packaging and their sources, material specifications, test methods, manufacturing and analytical equipment, production processes, manufacturing or packaging sites etc. A function that is independent from production (such as regulatory affairs, quality assurance, etc.) should have the responsibility and authority for the final approval of changes. Customers and, if necessary, regulatory authorities [for example for Drug Master Files (DMFs) or Certificates of Suitability to the European Pharmacopoeia (CEPs)] should be notified of significant changes from established production and process control procedures that may affect excipient quality (see also 7.2.3 and Appendix C). The IPECAmericas Significant Change Guide for Bulk Pharmaceutical Excipients provides criteria that the excipient manufacturer can use to determine when to involve the pharmaceutical customer, based on the likelihood that a proposed change will impact their drug product.
GMP Section Audited Item

4.3 Change Control 1. Change control procedure 2. Control of production changes 3. Independent approval of changes 4. Impact on qualification and validation 5. Change control log 6. Notification to customers & regulatory 1. 2. 3. 4. 5. 6.
Rating
Expected Observation
Change Control SOP in place Record and approval of changes Quality review of manufacturing changes Impact assessed by Quality Log (or equivalent) records all changes Change to filing considered, appropriate changes filed, and customers notified as per IPEC Significant Change Guide
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SOP 8
APPENDIX A 5 MANAGEMENT RESPONSIBILITY

5.1 Management Commitment Top management should demonstrate to the organization the importance it places on customer satisfaction and compliance with the appropriate regulations and standards. This should be accomplished through the development of a quality policy and establishment of quality objectives. Progress towards the documented quality objectives should be reviewed at planned intervals.
GMP Section Audited Item 5. . MANAGEMENT RESPONSIBILITY

5.1 Management Commitment 1. Commitment to customer satisfaction 2. Commitment to GMP compliance
Rating
1. Quality Policy in place 2. Objectives in place
5.2 Customer Focus It is the responsibility of top management to ensure that customer requirements are determined and met. The excipient manufacturer should permit the customer or their representative to conduct audits to review its quality management system, manufacturing processes, buildings and facilities.

5.2 Customer Focus 1. Customer requirements 2. Customer audit policy
Rating
1. Requirements available to appropriate personnel 2. Audit policy allows at least some audits conducted by customers or their representatives (third party)
5.3 Quality Policy Top management should demonstrate its commitment to the corporate quality policy and ensure that it is implemented within the operational unit. The quality policy should support continual improvement of the quality management system. Management should participate in the development of the company's quality policy and provide the resources necessary for its development, maintenance and deployment.

5.3 Quality Policy 1. Policy deployment, management support 2. Continual improvement
Rating
1. Posting, mailing, meetings, etc., and management actions 2. Policy implemented supports continual improvement
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APPENDIX A
5.4 Planning 5.4.1 Quality Objectives Top management should set objectives for adherence to GMP to ensure that the excipient manufacturer maintains and improves its performance. Objectives should be deployed throughout the organization and should be measurable and consistent with the quality policy. Quality Management System Planning Top management should provide adequate resources to ensure conformance to the provisions of this Guide. There should be a process for the identification of resources needed for adherence to GMP. A gap analysis based on audits by internal personnel, customers, regulatory agencies or outside contractors and this Guide could be used for the purpose of identifying resource requirements. Top management should ensure that the integrity of the quality management system is maintained when changes are planned and implemented.
5.4.2

5.4 Planning 5.4.1 Quality Objectives 1. Conformance objectives 5.4.2 Quality Measurement System Planning 1. Adequate resources
Rating
1. Written objectives
1. Observation that staffing, equipment and facilities are sufficient
5.5 Responsibility, Authority and Communication 5.5.1 Responsibility and Authority Responsibility and authority should be clearly defined by top management and communicated within the organization. It should be the responsibility of a unit independent of production, such as the quality unit, to: ensure quality-critical activities are undertaken as defined, approve suppliers of quality-critical materials and services, approve or reject raw materials, packaging components, intermediates and finished excipients, ensure that there is a review of production records to ensure that no errors have occurred or, if errors occur, that they are fully investigated, participate in reviewing and authorising changes to processes, specifications, procedures and test methods that potentially affect quality (see also 4.3) and in investigating failures and complaints, retain responsibility for approval or rejection of the excipient if it is produced, processed, packaged or held under contract by another company, develop and implement a self inspection programme of the quality management system.
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APPENDIX A
The excipient manufacturer may delegate some of the quality units activities to other personnel if appropriate controls (for example periodic audits, training and documentation) are in place. An organization chart by function should show inter-departmental relationships as well as relationships to top management of the company. Personnel who have an impact on excipient quality should have job descriptions. 5.5.2 Management Representative The excipient manufacturer should appoint a management representative with sufficient authority to ensure that the provisions of this Guide are properly implemented. The representative should periodically report to top management on conformance to the quality management system, including changing customer and regulatory requirements. Internal Communication The excipient manufacturer should ensure appropriate systems are established to communicate GMP and regulatory requirements, quality policies, quality objectives and procedures throughout the organization. The communication should also provide information about the effectiveness of the quality management system.
5.5.3
Top management should be notified in a timely manner of quality-critical situations, such as product retrievals, in accordance with a documented procedure.
Rating
5.5 Responsibility, Authority and Communication 5.5.1 Responsibility and Authority 1. Reporting relationship of Quality 1. Organizational chart showing Unit and Production independence from production 2. Job descriptions 2. Clear descriptions 3. Clarity of Quality Unit authority 3. Documentation of QA authority and and responsibilities, delegation responsibility 4. Batch release 4. Review of relevant records; confirm who has final authority for release 5.5.2 Management Representative 1. Periodic conformance report to 1. Management representative appointed and top management meetings scheduled to report on quality system conformance to management 5.5.3 Internal Communication 1. Quality system communication 1. Newsletter, email, meetings 2. Top management notification of 2. Evidence of problems reported to top quality critical issues management
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APPENDIX A
5.6 Management Review 5.6.1 General The top management of the company should hold periodic reviews of the quality management system to confirm the organizations continued conformance to this Guide. The review should be recorded and include assessing opportunities for improvement and the need for changes to the quality management system. 5.6.2 Review Input Management review inputs should include for example: results of internal and external audits, customer feedback of the company performance, product conformity and process performance, action items from the previous management review, customer complaints, status of corrective or preventive actions, changes that could affect the quality management system. Review Output The management review should identify the resources needed and opportunities presented for improvement of the quality management system and improvement of product conformance to customer and regulatory requirements. A record should be made of actions recommended and taken.
5.6.3

5.6 Management Review 5.6.1 General 1. Senior management quality system review 5.6.2 Review Input 1. Defined 5.6.3 Review Output 1. Resources and improvements identified
Rating
1. Documented management reviews conducted 1. Review includes audit findings, process capability, customer complaints, etc. 1. Meeting minutes identifies opportunities and need for improvement
6 RESOURCE MANAGEMENT
6.1 Provision of Resources There should be sufficient qualified personnel and resources (for example equipment, materials, buildings and facilities) to implement, maintain and improve the quality management system and to produce, package, test, store and release each excipient in a manner consistent with this Guide.
GMP Section Audited Item 6. RESOURCE MANAGEMENT

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Rating Expected Observation
APPENDIX A
6.1 Provision of Resources 1. Adequate resources
1. Evidence of sufficient qualified personnel, adequate facilities, space, and equipment
6.2 Human Resources 6.2.1 General Personnel performing work affecting the quality of excipients should have the appropriate combination of education, training and experience for their assigned tasks. Consultants advising on the design, production, packaging, testing or storage of excipients should have sufficient education, training and experience or any combination thereof to advise on the subject for which they are retained. Records should be maintained listing the name, address and qualifications of consultants and the type of service they provide. 6.2.2 Competence, Awareness and Training The excipient manufacturer should establish and maintain procedures for identifying training needs and providing the necessary training to personnel performing activities affecting excipient quality. Appropriate records of training should be maintained. Training should address the particular operations that the employee performs and GMP as it relates to the employees functions. Qualified individuals should conduct GMP training with sufficient frequency to ensure that employees remain familiar with applicable GMP principles. Management should establish adequate and continued personal hygiene training for personnel who handle materials so that they understand the precautions necessary to prevent contamination of excipients. The training program should ensure personnel understand that deviations from procedures may have an impact on the customers product quality. 6.2.3 Personnel Hygiene To protect excipients from contamination protective apparel such as head, face, hand and arm coverings should be worn as appropriate to the duties performed. Jewellery and other loose items, including those in pockets, should be removed or covered. Only authorised personnel should enter those areas of the buildings and facilities designated as limited access areas. Personnel should practice good sanitation and health habits. Any person shown to have an apparent illness or open lesions (by either medical examination or supervisory observation) that may adversely affect the safety or quality of the excipient should be excluded from direct contact with raw materials, packaging components, intermediates and finished excipients until the condition is corrected or determined by competent personnel not to jeopardise the safety or quality of the excipient. Personnel should be instructed to report to supervisory personnel any health conditions that may have an adverse effect on excipients.
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APPENDIX A
The storage and use of food, drink, personal medication, tobacco products or similar items should be restricted to certain designated locations separate from manufacturing areas.

6.2 Human Resources 6.2.1 General 1 Education, training, experience 2 Consultant qualifications 6.2.2 Competence, Awareness and Training 1. Adequate training, experience, & qualifications 2. Training SOP 3. Training program 4. Trainer qualifications 5. GMP training records 6. GMP training frequency 7. Measure of training effectiveness 8. Communicating changing regulations 6.2.3 Personnel Hygiene 1. Personal hygiene training 2. Clothing 3. Reporting of illness 4. Loose items like jewelry and pens 5. Consumption of food, beverage & tobacco products 6. Access control 6.3 Infrastructure
1. Records, observations and responses 2. Qualifications documented
1. Program for training employees; training records and qualifications 2. SOP describing training program 3. Training and content documented 4. Trainer qualifications documented 5. Records of attendance and content 6. Frequency of training in GMPs 7. Appropriate measurements in place 8. Assigned responsibility for monitoring regulations and communicating changes 1. Training program including reporting illness 2. Written gowning requirements 3. Procedure for reporting 4. Observation of loose items 5. Designated areas for consumption 6. Policy on escorting visitors
The infrastructure should be managed, operated, cleaned and maintained in accordance with GMP principles to ensure excipient quality and to avoid contamination (including, where critical to excipient quality, control of particulate matter, microbiological control and control of water quality).
6.3.1 Buildings and Facilities The prevention of contamination should be considered in the design of the manufacturing processes and facilities, particularly where the excipient is exposed. Buildings and facilities used in the production, processing, packaging, testing or storage of an excipient should be maintained in a good state of repair and should be of suitable size, construction and location to facilitate cleaning, maintenance and correct operation appropriate to the type of processing. Manufacturing processes associated with the production of highly sensitizing or toxic products (for example herbicides, pesticides etc.) should be located in dedicated facilities or use equipment separate from that used for excipient manufacture. If this is not possible then appropriate measures (for example
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APPENDIX A
cleaning, inactivation) should be implemented to avoid cross-contamination. The effectiveness of these measures should be demonstrated. There should be adequate facilities for the testing of raw materials, packaging components, intermediates and finished excipients. 6.3.2 Equipment Equipment used in the production, processing, packaging, testing or storage of an excipient should be maintained in a good state of repair and should be of suitable size, construction and location to facilitate cleaning, maintenance and correct operation, depending on the type of processing (for example batch versus continuous). Equipment should be commissioned before use to ensure that it is functioning as intended. Where equipment is located outdoors there should be suitable control to minimize the risk to excipient quality from the environment (for example processing within a closed system). 6.3.2.1 Equipment Construction Process equipment should be constructed so that contact surfaces will not be reactive, additive or absorptive and thus not alter the quality of the excipient. Substances required for operation, such as lubricants or coolants, should preferably not come into contact with raw materials, packaging materials, intermediates or finished excipients. Where contact is possible, substances suitable for use in food applications should be utilised. Equipment should be designed to minimise the possibility of contamination caused by direct operator contact in such activities as the unloading of centrifuge bags, use of transfer hoses (particularly those used to transfer powders) and the operation of drying equipment and pumps. The sanitary design of transfer and processing equipment should be evaluated. Equipment with moving parts should be assessed with regard to the integrity of seals and packing materials to control the risk of contamination. 6.3.2.2 Equipment Maintenance Documented procedures should be established and followed for maintenance of critical equipment used in the production, processing, packaging, testing or holding of the excipient. There should be records of the use and maintenance of quality-critical equipment. These records can be in the form of a log, computer database or other appropriate documentation. 6.3.2.3 Computer Systems Computer systems that may impact upon excipient quality should have sufficient controls for operation and maintenance and to prevent
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unauthorised access or changes to computer software, hardware or data, including: systems and procedures that show the equipment and software are performing as intended, procedures for checking the equipment at appropriate intervals, retention of suitable back-up or archival systems such as copies of the program and files, assurance that changes are verified and documented and only made by authorised personnel. 6.3.3 Utilities Utilities (for example nitrogen, compressed air, steam etc.) used in the production, storage or transfer of materials that could impact excipient quality should be assessed and appropriate action taken to control the risk of contamination and cross-contamination. Water Water used in the manufacture of excipients should be demonstrated to be of a suitable quality for its intended use. Unless otherwise justified process water should, at a minimum, meet WHO guidelines for drinking (potable) water quality. If drinking (potable) water is insufficient to assure quality or tighter chemical and/or microbiological water quality specifications are required, appropriate controls and specifications should be set, for example physical and chemical attributes, total microbial counts, limits on objectionable organisms and/or endotoxins. Where water used in the process is treated by the manufacturer to achieve a defined quality the treatment process should be specified and monitored with appropriate action limits. Water that comes into contact with the excipient should be supplied under continuous positive pressure (or other means of preventing back flow) in a system free of defects to control the risk of contamination to the excipient.
6.3.4
6.3 Infrastructure (Facilities and Equipment) 6.3.1 Building and Facilities 1. Space 1. Evidence of adequate space 2. Contamination control 2. Protection from environmental contaminants 3. Toxic products 3. Presence or absence of nearby toxic material or operations 4. Environmental controls 4. Adequate preventive measures 5. Laboratory facilities 5. Adequate lab facilities 6. State of repair 6. Evidence of adequate maintenance 6.3.2 Equipment 1. Commissioning 1. Demonstrate suitability for purpose
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2. Maintenance 3. Outdoor equipment 6.3.2.1 Equipment Construction 1. Contact surfaces 2. Lubricants, coolants, etc. 3. Design to minimize contamination 6.3.2.2 Equipment Maintenance 1. Procedures 2. Records 3. Hand over/hand back 6.3.2.3 Computer Systems 1. Access controls 2. Change controls 3. Consistent function 4. Back up, disaster recovery 6.3.3 Utilities 1. Risk of contamination 6.3.4 Water 1. Specification 2. Treatment and monitoring 2. Evidence of proper maintenance 3. No exposure where processing outdoors 1. Unreactive and minimize contamination 2. Use of food grade materials for operating equipment 3. Protect excipient from contamination from personnel 1. SOP for periodic inspection of equipment 2. Records to create equipment use log for critical equipment 3. Return of equipment to service approved and documented 1. Logon ID and Passwords 2. Only authorized changes and log 3. Computer and Software operate as expected 4. Evidence systems are backed up 1. Shown not to contaminate excipient 1. Contact water quality o Potable source or justify 2. DI, DM, RO, & distillation systems require periodic sanitization and maintenance & periodic testing o Quality standard & action limit o Evaluation of poor quality 3. Confirm positive pressure and measures to prevent back flow
3. Positive pressure/back flow
6.4 Work Environment Where the excipient is exposed during manufacture it should be in an appropriate environment to minimise contamination. The manufacturer should apply suitable controls to maintain that environment. 6.4.1 Air Handling Where an air handling system is installed to provide protection to the excipient, the excipient manufacturer should demonstrate its effectiveness. Excipient production unit air handling systems should be designed to prevent cross-contamination. For dedicated areas processing the same excipient it is permissible to recycle a portion of the exhaust air back into the same area. The adequacy of such a system for multi-use areas, especially if several products are processed simultaneously, should be assessed for potential cross-contamination.
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6.4.2 Controlled Environment A controlled environment may be necessary to avoid contamination or degradation caused by exposure to heat, air or light. The degree of protection required may vary depending on the stage of the process. Special environments required by some processes should be monitored to assure product quality (for example inert atmosphere or protection from light). Where an inert atmosphere is required, the gas should be treated as a raw material. If interruptions in the special environment occur adequate evidence and appropriate rationale should be documented to show that such interruptions have not compromised the quality of the excipient. Such environmental concerns become increasingly important following purification of the excipient. 6.4.3 Cleaning and Sanitary Conditions Adequate cleanliness is an important consideration in the design of excipient manufacturing facilities. Buildings used in the production, processing, packaging or holding of an excipient should be maintained in an appropriately clean and sanitary condition according to the type of processing conducted (for example open/closed systems). Where maintenance of clean and sanitary conditions is critical to excipient quality, documented procedures should assign responsibility for cleaning and sanitation, describing in sufficient detail the cleaning schedules, methods, equipment and materials to be used in cleaning the buildings and facilities. These procedures should be followed and cleaning should be documented. Waste should be segregated and disposed of in a timely and appropriate manner. If waste is not disposed of immediately, it should be suitably identified. 6.4.4 Pest Control Buildings should be free from infestation by rodents, birds, insects and other vermin. Some raw materials, particularly botanicals, may contain some unavoidable contamination, such as rodent or other animal filth or infestation. The manufacturer should have sufficient control methods to prevent the increase of such contamination or infestation in holding areas and its spread to other areas of the plant. 6.4.5 Lighting Adequate lighting should be provided to facilitate cleaning, maintenance and proper operations. Drainage In areas where the excipient is open to the environment, drains should be of adequate size and, where connected directly to a sewer, should be provided with an air break or other mechanical device to prevent back-siphoning. Washing and Toilet Facilities Adequate personal washing facilities should be provided, including hot and cold water, soap or detergent, air dryers or single service towels and clean toilet
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6.4.6
6.4.7
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facilities easily accessible to working areas. Adequate facilities for showering and/or changing clothes should be provided, where appropriate.
GMP Section Audited Item 6.4 Work Environment

6.4.1 Air Handling 1. Effectiveness 2. Recirculation 6.4.2 Controlled Environment 1. Required 2. Monitoring 3. Deviations 6.4.3 Cleaning and Sanitary Conditions 1. Appropriately clean 2. Procedures, schedules 3. Waste control 6.4.4 Pest Control 1. Free of infestation 2. Contractor controls 3. Records, review of effectiveness 6.4.5 Lighting 1. Adequate 6.4.6 Drainage 1. Adequate 2. Air break 6.4.7 Washing and Toilet Facilities 1. Adequate facilities
1. Demonstrated efficacy, adequate filters and maintained 2. Documented requirements 1. Temp, humidity, and pressure specified if control required 2. Evidence the environment is monitored 3. Review of effect on excipient and document 1. Clean and orderly appearance 2. SOP for cleaning and records documenting cleaning 3. Proper storage and removal 1. No signs of infestation 2. Adequate controls in place 3. Controls documented 1. Sufficient lighting with adequate protection (diffuser, screen, etc.) 1. No pooling where excipient exposed 2. Air break or mechanical device in-place 1. Readily accessible with evidence of periodic cleaning and personal hygiene signs 2. Clean with running water, soap, and single use towels or air dryer
2. Clean
PRODUCT REALIZATION
7.1 Planning of Product Realisation The excipient manufacturer should plan and develop the processes and controls needed for product manufacture. These plans and controls should be appropriate to the production process, excipient specification, equipment and facilities used in the manufacture of the product. Key aspects of the planning of a suitable process and its controls should include as appropriate:
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documented testing programs for quality-critical materials including excipients that include appropriate specifications, sampling plans, test and release procedures, generation and maintenance of records (see also 4.2.4) that provide evidence that these plans have been realised as intended and that enable traceability to be demonstrated (see also 7.5.3.1), provision of resources to implement these plans, environmental and hygiene control programs to minimise contamination.
GMP Section Audited Item 7. PRODUCT REALIZATION

7.1 Planning of Product Realization 1. Process flow diagram 2. Critical parameters 3. Batch or continuous 4. Multi-purpose 5. Equipment & lines ID 7.2 Customer-related Processes 7.2.1 1. 2. 3. 4. 5.
Available Identification and justification Batch or continuous identified Other products produced Equipment and lines labeled
Determination of Requirements Related to the Product The excipient manufacturer should determine the excipient quality, labelling and delivery requirements of the customer. Additional requirements, whether customer-specific, legal or regulatory (for example pharmacopoeia material and general monographs), should be agreed by both parties. Requirements not stated by the customer but necessary for specified or intended use, where known, should be considered. Review of Requirements Related to the Product The excipient manufacturer and customer should mutually agree upon the requirements identified in 7.2.1 before supply commences. The manufacturer should have the facility and process capability to meet consistently the mutually agreed specifications. Where the requirements determined in 7.2.1 are changed, this review should be repeated before supply recommences. Customer Communication There should be provision for providing accurate and pertinent communication to the customer. Master copies of documents such as specifications and technical reports should be controlled documents. Provision should be made for replying to customer enquiries, contracts and order handling requirements. Customer feedback and complaints should be documented. Customers should be notified of significant changes (see also 4.3). For additional change notification information refer to IPEC-Americas Significant Change Guide for Bulk Pharmaceutical Excipients.
7.2.2
7.2.3

7.2 Customer-related Processes 7.2.1 Determination of Requirements Related to the Product
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1. Customer requirements 2. Agreed additional requirements 7.2.2 Review of Requirements Related to the Product 1. Mutually agreed specifications 2. Contract review 7.2.3 Customer Communication 1. Implementation of customer requirements 2. Notification to customers of significant changes 1. Procedure for review and approval 2. Identification of other requirements
1. Assure specifications and other requirements are in-place 2. Allow impacted parties to review 1. Prompt incorporation of customer requested change 2. Agreement to notify customers of significant changes
7.3 Design and Development ISO 9001 includes requirements for ensuring control over design and development activities. Companies involved in such activities are recommended to follow the requirements of ISO 9001. Full GMP is not always applicable during the design and development of new excipients and/or manufacturing processes. However, development batches of excipients that are intended for use in drug products should be manufactured in accordance with the applicable provisions of this Guide.

7.3 Design and Development 1. Technology transfer
1. Procedure for implementing technology transfer to production
7.4 Purchasing 7.4.1 Purchasing Process Excipient manufacturers should have a system for selecting and approving suppliers of quality-critical materials and services (for example subcontract manufacturers and laboratories). Supplier approval by the quality unit should require an evaluation of the suppliers quality management system, including adequate evidence that they can consistently meet agreed requirements. This may require periodic audits of the suppliers manufacturing facility. Records of these activities should be maintained. Materials should be purchased against an agreed specification from approved suppliers. 7.4.2 Purchasing Information Purchasing agreements should describe the material or service ordered including, where critical to excipient quality, the following: the name, type, class, style, grade, item code number or other precise identification traceable to the raw material and packaging specifications, drawings, process requirements, inspection instructions and other relevant technical data, including requirements for approval or qualification of product, procedures, process equipment and personnel,
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adherence to the appropriate sections of this Guide for relevant contract manufacturers or laboratories, a statement to notify the excipient manufacturer of significant changes in quality-critical raw materials.
7.4.3
Verification of Purchased Product There should be procedures for the approval and release of quality-critical material. Upon receipt, quality-critical materials should be placed in quarantine and should not be used prior to acceptance. Effective quarantine can be established with suitable identifying labels, signs and/or other manual documentation systems. When quarantine and stock control are managed with computer systems in lieu of a physical stock control, then system controls should prevent the use of unreleased material. Quarantine may not be feasible for materials supplied via pipelines. In these cases the excipient manufacturer should establish an agreement with the supplier so that they are notified of material that does not meet specification. Sampling activities should be conducted under defined conditions, in accordance with a defined sampling method and using procedures designed to prevent contamination and cross-contamination. Quality-critical materials used in the manufacture of an excipient should be tested or otherwise verified prior to use. Verification should include availability and a check of the supplier certificate of analysis and, wherever feasible, at least an identification test. Testing schedules should be organised to separate those tests that are routine from those that are performed infrequently or only for new suppliers. Bulk deliveries should have additional controls to assure material purity and freedom from contamination (for example dedicated tankers, tamper-evident seals, a certificate of cleaning, analytical testing and/or audit of the supplier). These procedures, activities and results should be documented.

7.4 Purchasing 7.4.1 Purchasing Process 1. Qualification and control of suppliers 2. Approved supplier list 3. Audit of key suppliers 4. Selection and control of subcontractors 5. Follow-up of audit corrective actions 6. Material specifications
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1. SOP for supplier selection and approval 2. Maintenance of list 3. ID of key suppliers and evidence of audits 4. SOP for subcontractor assessment and oversight 5. Track audit corrective actions 6. Written raw material specifications
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7. BSE/TSE, etc. risks 7.4.2 Purchasing Information 1. Purchasing agreement 2. Supplier review of specifications 3. Supplier notification of significant change 7.4.3 Verification of Purchased Product 1. Procedures for approval and release 2. Quarantine 3. Sampling procedures and conditions 4. Testing/verification 5. Bulk deliveries 7.5 Production and Service Provision 7.5.1 Control of Production and Service Provision Production activities should be carried out under controlled conditions (see also section 7.1). Specific examples of important controls, some of which may not be applicable to all excipient manufacturers, are illustrated in the following sections. 7.5.1.1 Production Instructions and Records Production instructions and records are required but may differ for the type of operation, for example batch versus continuous processes. There should be a controlled document that describes how the excipient is produced (for example master production instructions, master production and control records, process definitions etc.). For batch processes an accurate reproduction of the appropriate master production instructions should be issued to the production area. For continuous processes a current processing log should be available. Records should be available for each batch of excipient produced and should include complete information relating to the production and control of each batch. For continuous processes the batch and its records should be defined (for example based on time or defined quantity). Records may be in different locations but should be readily retrievable. Records for both batch and continuous processing, where critical to excipient quality, should include: date/time each step was completed or date/time log of key parameters, identification of persons performing and directly supervising or checking each significant step, operation or control parameter, identification of major equipment and lines used, 7. Acknowledgement of animal sourced materials, allergens, etc. 1. Written agreement 2. Acknowledgement specifications are approved 3. Written agreement to notify of significant change 1. Approval includes QC and confirmation of COA 2. Quarantine appropriate & maintained 3. Conducted with a defined plan under appropriate conditions 4. Adequate samples taken and tested 5. Dedicated or certified clean vehicles
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material inputs to enable traceability, for example batch number and quantities of raw material/intermediate, time it was added, etc., in-process and laboratory control results, the quantity produced for the defined batch and a statement of the percentage of theoretical yield, unless not quantifiable (for example as in some continuous processes), inspection of the packaging and labelling area before and after use, labeling control records, description of excipient product containers and closures, description of sampling performed, failures, deviation and their investigations, results of final product inspection.
7.5.1.2 Equipment Cleaning The manufacturer should design and justify cleaning and sanitization procedures and provide evidence of their effectiveness. In multi-purpose plants the use of the model product approach (groups of product of similar type) may be used in justifying a suitable procedure. Cleaning and sanitization procedures should be documented. They should contain sufficient detail to allow operators to clean each type of equipment in a reproducible and effective manner. There should be a record confirming that these procedures have been followed. Equipment and utensils should be cleaned and sanitised where critical to excipient quality and at appropriate intervals to prevent contamination and cross-contamination of the excipient. The cleaning status of equipment should be recorded appropriately. Where multi-purpose equipment is in use it is important to be able to determine previous usage when investigating cross-contamination or the possibility of such contamination (see also 7.5.1.7). During a production campaign incidental carry-over frequently occurs and is acceptable usually since clean-up between successive batches of the same excipient is not normally required to maintain quality levels. Products that leave residues that cannot be effectively removed should be produced in dedicated equipment. For continuous processing the frequency of equipment cleaning should be determined by the manufacturer and justified. 7.5.1.3 Recovery of Solvents, Mother Liquors and Second Crop Crystallizations Where solvents are recovered and reused in the same process or different processes they should meet appropriate standards prior to reuse or mixing with other approved material. Mother liquors or filtrates containing recoverable amounts of excipient, reactants or intermediates are frequently reused. Such processes should be documented in the production records or logs to enable traceability.
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7.5.1.4 In-process Blending or Mixing In process blending or mixing to assure batch uniformity or to facilitate processing should be controlled and documented. If the intent of the operation is to ensure batch uniformity it should be performed so as to assure homogenous mixing of materials to the extent feasible and should be reproducible from batch to batch. 7.5.1.5 In-process Control In-process inspection and testing should be performed based upon monitoring the process or actual sample analysis at defined locations and times. Sampling methods should be documented to ensure that the sample is representative and clearly labelled. In-process samples should not be returned to production for incorporation into the final batch. The results of in-process tests should be recorded and should conform to established process parameters or acceptable tolerances. Work instructions should define the procedure to follow and how to utilise the inspection and test data to control the process. There should be defined actions to be taken when the results are outside specified limits. Where approval to continue with the process is issued within the production department, the specified tests should be performed by trained personnel and the results recorded. 7.5.1.6 Packaging and Labeling Procedures should be employed to protect the quality and purity of the excipient when it is packaged and to assure that the correct label is applied to all containers. Packaging and labelling operations should be designed to prevent mix-ups. Procedures should be implemented to ensure that the correct labels are printed and issued and that the labels contain the correct information. The procedure should also specify that excess labels are immediately destroyed or returned to controlled storage. Excess labels bearing batch numbers should be destroyed. Packaging and labelling facilities should be inspected immediately before use to ensure that materials that are not required for the next packaging operation have been removed. Where excipients are labelled on the packaging line, packaged in preprinted bags or bulk-shipped in tank cars there should be documentation of the system used to satisfy the intent of the above procedures. 7.5.1.7 Records of Equipment Use Records of quality-critical equipment use should be retained. These records should allow the sequence of cleaning, maintenance and production activities to be determined.
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APPENDIX A GMP Section Audited Item Rating Expected Observation
7.5 Production and Service Provision 7.5.1 Control of Production and Service Provision 7.5.1.7 Production Instructions and Records 1. Controlled master batch 1. Controlled document instructions 2. Retrievable batch records 2. Proper storage and retrieval of records 3. Suitable details 3. Record shows instructions were followed 7.5.1.8 Equipment Cleaning 1. Dedicated or controls for 1. Measures to prevent cross-contamination cross-contamination 2. Cleaning effectiveness and 2. Evidence of effectiveness of cleaning justification 3. Documentation of cleaning 3. Records show sequence of cleaning and use 4. Storage of utensils and 4. Utensil storage protects from sampling devices environmental contamination 5. Continuous processes, 5. Frequency of cleaning justified frequency of cleaning 7.5.1.9 Recovery of Solvents 1. Controls in place 1. Specification in place and recovered solvent is tested, including continuous processes 2. Traceability 2. Adequate records for mother liquors and filtrates 7.5.1.10In-Process Blending/Mixing 1. Blending procedures 1. Complete instructions 2. Defined blending parameters 2. Blending parameters or spec to confirm quality of blend 3. Part containers/tails 3. Fate of short containers or tailings 7.5.1.11In-Process Control 1. Program 1. Instructions with set-points, limits 2. Sampling procedures 2. Clear, appropriate instructions 3. Results recorded 3. Records show conformance 4. Control actions 4. Instructions how to control process and SOP when material fails 7.5.1.12Packaging and Labeling 1. Procedures 1. SOP includes confirming area is clear and ready for packaging 2. Label control 2. Security to prevent misuse 3. Mix-up prevention 3. Measures to assure correct label is used 7.5.1.13Records of Equipment Use 1. Sequence of activities 1. Production, maintenance, cleaning sequence documented in equipment log or equivalent records
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7.5.2 Validation of Processes for Production and Service Provision An important factor in the assurance of product quality includes the adequate design and control of the manufacturing process because product testing alone is not sufficient to reveal variations that may have occurred. Each step of the manufacturing process should be controlled to the extent necessary to ensure that the excipient meets established specifications. The concept of process validation is a key element in ensuring that these quality assurance goals are met. The process reactions, operating parameters, purification steps, impurities and key tests needed for process control should be documented, thus providing the basis for validation. The full validation program that is typically performed in the pharmaceutical industry may not always be carried out by the excipient manufacturer. However, the excipient manufacturer should demonstrate the consistent operation of each manufacturing process, for example through process capability studies, development and scale-up reports etc.

7.5.2 Validation of Processes for Production and Service Provision 1. Process consistency 7.5.3
1. Process demonstrated to be capable
Identification and Traceability 7.5.3.1 Traceability Quality-critical items, for example raw materials, packaging materials, intermediates and finished excipients should be clearly identified and traceable through records. These records should allow traceability of the excipient both upstream and downstream. Identification of raw materials used in batch production processes should be traceable through the batch numbering system or other appropriate system. Identification of raw materials used in excipients produced by continuous processing should indicate the timeframe during which a particular batch of raw material was processed through the plant. Raw materials, including solvents, are sometimes stored in bulk tanks or other large containers, making precise separation of batches difficult. Nevertheless, the use of such materials should be documented in production records. 7.5.3.2 Inspection and Test Status There should be a system to identify the inspection status of qualitycritical items including raw materials, packaging materials, intermediates and finished excipients. Whilst storing materials in identified locations is preferred, any means that clearly identifies the test status is satisfactory. Continuously-fed materials may need special consideration in order to satisfy these requirements.
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7.5.3.3 Labeling Labeling for excipient packages is subject to national and international regulatory requirements, which may include transportation and safety measures. As a minimum, labels should include: the name of the excipient and grade if applicable, the excipient manufacturers and/or distributors name, the batch number from which the complete batch history can be determined, special storage conditions, if applicable.

7.5.3 Identification and Traceability 7.5.3.1 Traceability 1. Material to their manufacturer 2. Material through production 3. Unique batch numbering 4. Batch definition for continuous processing 5. Traceability of reprocessed material 6. Origin of manufacturing site 7.5.3.2 Inspection & Test Status 1. Approval of materials & packaging 2. Controls for unapproved materials 3. Identification of containers and equipment 4. Status identification 5. Identification of unlabeled container 6. Evaluation of raw materials beyond expiration or use date 7. Quarantine control 7.5.3.3 Labeling 1. Excipient labeling content 2. Special storage condition labeling 7.5.4
1. Records show source of material 2. Material lot ID part of production record 3. Batch clearly defined with unique excipient lot number 4. Definition of batch 5. Adequate records 6. Identification of site of manufacture 1. QC approval 2. Physical segregation or computer control to prevent use 3. All equipment and containers identified 4. Identification of status thru labels or computer system 5. Information to ID content of unlabeled containers 6. SOP for evaluation of raw materials beyond expiration or use date and Quality approval 7. Adequate physical separation, status labels or computer system 1. Name, grade, quantity, lot number and manufacturer 2. If needed on label including expiry date
Customer Property The excipient manufacturer should establish and maintain procedures for verification, storage and maintenance of customer-supplied materials intended for incorporation into the customer's excipient. Verification by the manufacturer
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does not relieve the customer of the responsibility to provide an acceptable material. Material that is lost damaged or is otherwise unsuitable for use should be recorded and reported to the customer. In this case, procedures should be in place for acceptable disposition and replacement of the material. The manufacturer should also make provisions to protect other real and intellectual property that is provided by the customer (for example test equipment, test methods and specifications).

7.5.4 Customer Property 1. Procedure 2. Agreements for confidential information 7.5.5 Preservation of Product
1. Controls to prevent use in other than intended customers product(s) 2. Confidentiality maintained
7.5.5.1 Handling, Storage and Preservation Excipients, intermediates and raw materials should be handled and stored under appropriate conditions of temperature, humidity and light so that their identity, quality and purity are not affected. Outdoor storage of raw materials (for example acids, other corrosive substances or explosive materials) or excipients is acceptable provided the containers give suitable protection against deterioration or contamination of their contents, identifying labels remain legible and containers are adequately cleaned prior to opening and use. Records of storage conditions should be maintained if they are critical for the continuing conformance of the material to specification. 7.5.5.2 Packaging Systems An excipient packaging system should include the following features: documented specifications and examination or testing methods, cleaning procedures where containers are reused, tamper-evident seals, containers that provide adequate protection against deterioration or contamination of the excipient during transportation and recommended storage, containers that do not interact with or contaminate the excipient, storage and handling procedures which protect containers and closures and minimise the risk of contamination, damage or deterioration and which will avoid mix-ups (for example between containers that have different specifications but are similar in appearance). If returnable excipient containers are re-used, previous labelling should be removed or defaced. If the containers are repetitively used solely for the same excipient, previous batch numbers or the entire label should be removed or completely obliterated.
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7.5.5.3 Delivery and Distribution Identification and traceability of quality-critical aspects are required of excipient manufacturers. Distribution records of excipient shipments should be kept. These records should identify, by excipient batch, where and to whom the excipient was shipped, the amount shipped and the date of shipment so as to facilitate retrieval if necessary. Where excipients are handled by a series of different distributors, it should be possible to trace them back to the original manufacturer and not just to the previous supplier. The manufacturer should maintain the integrity and the quality of the product after final inspection and test. Where contractually specified, this protection should be extended to include delivery to the final destination. Excipients should only be supplied within their expiry and/or retest period.

7.5.5 Preservation of Product 7.5.5.1 Handling, Storage, and Preservation 1. Appropriate conditions and record 2. Outside storage 3. Bulk storage dispensing
4. Stock rotation 7.5.5.2 Packaging Systems 1. Adequate protection to excipient 2. Storage of packaging components 3. Reusable packaging 4. Bulk container cleanliness 5. Bulk container seals 6. Tamper evident Seals 7.5.5.3 Delivery and Distribution 1. Distribution records 2. Traceable to consignee 3. Retrieval or market withdrawal procedure
1. Documentation of conditions where specified 2. Protection of package & label 3. Procedures in place to assure dispensing systems are accurate and to prevent shipment of unreleased excipient 4. Procedures to assure FIFO 1. Documented study showing packaging protects excipient 2. Packaging stored to prevent deterioration 3. Validation of container cleaning and label removal 4. Documentation of cleanliness and prior load 5. All openings sealed 6. Package seal would show tampering 1. Adequate shipping records 2. Verifiable documentation 3. Procedure and periodic test to demonstrate effectiveness
7.6 Control of Measuring and Monitoring Devices Measuring and test equipment, including computerised systems, identified as being quality-critical should be calibrated and maintained. This includes in-process instruments as well as test equipment used in the laboratory. The control program should include the standardisation or calibration of instruments and equipment at suitable intervals in accordance with an established documented program. This program should contain
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specific directions, schedules, limits for accuracy and precision and provisions for remedial action in the event that accuracy and/or precision limits are not met. Calibration standards should be traceable to recognised national or Compendial standards as appropriate. Instruments and equipment not meeting established specifications should not be used and an investigation should be conducted to determine the validity of the previous results since the last successful calibration. The current calibration status of quality-critical equipment should be known and verifiable to users.

7.6 Control of Measuring and Monitoring Devices 1. Calibration procedures, records, and status 2. Standards-handling and storage
1. SOP describes all activities 2. Stored and handled in-house to prevent deterioration and traceable to a national standard 3. Established calibration frequency and limits, and removal from service if out of calibration or beyond due date 4. Actions to take if out of calibration
3. Frequency and limits
4. Out of calibration actions
8 MEASUREMENT, ANALYSIS AND IMPROVEMENT

8.1 General The organization should plan and implement the monitoring, measurement and improvement activities required to demonstrate conformity of the excipient to customer requirements and to ensure conformity of the quality management system to this Guide. The organization should evaluate opportunities for improvements through the measurement and analysis of product and process trends.
GMP Section Audited Item Expected Observation 8. MEASUREMENT, ANALYSIS AND IMPROVEMENT
8.1 General 1. Quality management processes 1. Monitoring and measuring activities including excipient quality
Rating
8.2 Monitoring and Measurement 8.2.1 Customer Satisfaction The excipient manufacturer should establish measurement activities to assess customer satisfaction. Such measurements can include customer complaints, return of excipients and customer feedback. This information should drive activities that strive to continuously improve customer satisfaction.
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APPENDIX A
8.2.2 Internal Audit The excipient manufacturer should carry out a comprehensive system of planned and documented internal quality audits. These should determine whether quality activities comply with planned arrangements and the effectiveness of the quality management system. Audits should be scheduled on the basis of the status and importance of the activity. Audits and follow-up actions should be carried out in accordance with documented procedures. Audit results should be documented and discussed with management personnel having responsibility in the area audited. Management personnel responsible for the area audited should take corrective action on the nonconformities found. Appendix A, Auditing Considerations will be of assistance in establishing an internal audit program. 8.2.3 Monitoring and Measurement of Processes The excipient manufacturer should identify the tests and measurements necessary to adequately control manufacturing and quality management system processes. Where critical to excipient quality, techniques that are used to verify that the processes are under control should be established. Corrective action should be taken to ensure the excipient meets requirements when deviations from planned results occur. Periodic reviews of key indicators such as process quality attributes and process failures should be conducted to assess the need for improvements. . 8.2.4 Monitoring and Measurement of Product The excipient manufacturer should establish the test methods and procedures to ensure the product consistently meets specifications. Analytical methods should be fit for purpose. The analytical methods may be those included in the current edition of the appropriate pharmacopoeia or another accepted standard. However, the methods may also be non-Compendial. If the excipient manufacturer claims that their product is in compliance with a pharmacopoeia or an official compendium, then: non-Compendial analytical tests should be demonstrated to be equivalent to those in the compendia, it should comply with applicable general chapters and notices. 8.2.4.1 Laboratory Controls Laboratory Controls should include complete data derived from tests necessary to ensure conformance with specifications and standards including: a description of the sample received for testing together with the material name, batch number or other distinctive code and date the sample was taken, a statement referencing each test method used,
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APPENDIX A
a record of raw data secured during each test including graphs, chromatograms, charts and spectra from laboratory instrumentation, identified to show the specific material and batch tested, a record of calculations performed in connection with the test, test results and how they compare with established specifications, a record of the person who performed each test and the date(s) the tests were performed.
There should be a documented procedure for the preparation of laboratory reagents and solutions. Purchased reagents and solutions should be labelled with the proper name, concentration and expiry date. Records should be maintained for the preparation of solutions including the name of the solution, date of preparation and quantities of material used. Volumetric solutions should be standardised according to an internal method or by using a recognised standard. Records of the standardisation should be maintained. Where used, primary reference reagents and standards should be appropriately stored and need not be tested upon receipt provided that a certificate of analysis from the supplier is available. Secondary reference standards should be appropriately prepared, identified, tested, approved and stored. There should be a documented procedure for the qualification of secondary reference standards against primary reference standards. The re-evaluation period should be defined for secondary reference standards and each batch should be periodically re-qualified in accordance with a documented protocol or procedure. 8.2.4.2 Finished Excipient Testing and Release Finished excipient testing should be performed on each batch to ensure that the excipient conforms to documented specifications. There should be a procedure to ensure that appropriate manufacturing documentation, in addition to the test results, is evaluated prior to release of the finished excipient. The quality unit should be responsible for the release of the finished excipient. For excipients produced by continuous processes assurance that the excipient conforms to documented specifications may be achieved through the results of in-process testing or other process control records. 8.2.4.3 Out-of-Specification Test Results Out-of-specification (OOS) test results should be investigated and documented according to a documented procedure. Retest sample results may only be used to replace the original test result if it is demonstrated that the original result is erroneous based on a documented investigation. When statistical analysis is used, both the original and retest data must be included. The OOS procedure should define which statistical techniques are to be used and under what circumstances.
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APPENDIX A
These same principles apply when the sample is suspected of not being representative of the material from which it was taken. 8.2.4.4 Retained Samples Where practical, a representative sample of each batch of the excipient should be retained. The retention period should be appropriate to the expiry or re-evaluation date. The retained samples should be stored and maintained in such a manner that they are readily retrievable in facilities that provide a suitable environment. The sample size should be at least twice the amount required to perform complete specification testing. 8.2.4.5 Certificates of Analysis The organization should provide certificates of analysis to the required specification for each batch of excipient. More details on the suitable contents of a certificate of analysis can be found in the IPEC-Americas Certificate of Analysis Guide for Bulk Pharmaceutical Excipients and the UK Guidance on Certificates of Analysis from The Rules and Guidance for Pharmaceutical Manufacturers and Distributors. 8.2.4.6 Impurities Where possible, excipient manufacturers should identify and set appropriate limits for impurities. The limits should be based upon appropriate safety data, limits as described in official compendia or other requirements and sound GMP considerations. Manufacturing processes should be adequately controlled so that the impurities do not exceed such established limits. Many excipients are extracted from or purified using organic solvents. These solvents are normally removed by drying. It is important that excipient specifications include tests and limits for solvent residues. 8.2.4.7 Stability While many excipient products are stable and may not require extensive testing to assure stability, the stability of excipients is an important factor contributing to the overall quality of the drug product. For excipients that have been on the market for a long time historical data may be used to indicate stability. Where historical data do not exist a documented testing and/or evaluation program designed to assess the stability characteristics of the excipient should be undertaken. The results of such stability testing and/or evaluation should be used in determining appropriate storage conditions and retest or expiry dates. The testing program should include the following: the number of batches, sample sizes and test intervals, storage conditions for samples retained for testing, suitable stability-indicating test methods, storage of the excipient in containers that simulate the market container, where possible. The stability of excipients may be affected by undetected changes in raw materials or subtle changes in manufacturing procedures or storage
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APPENDIX A
conditions. Excipients may also be shipped in a variety of packaging types that can affect their stability (for example plastic or glass bottles, metal or plastic drums, bags, tank cars or other bulk containers, etc.). Some excipients may be available in different grades (for example various molecular weights of a polymer or different monomer ratios, different particle sizes, bulk densities etc.) or may be mixtures of other excipients. These excipients may be very similar to others within a product group. Minor quantitative differences of some of the components may be the only significant variation from one product to another. For these types of excipients, a model product approach may be appropriate to assess the stability of similar excipients. Stability studies of this type should involve selection of several model products that would be expected to simulate the stability of the product group being assessed. This selection should be scientifically sound and documented. Data from stability studies of these model products can be used to determine theoretical stability for similar products. 8.2.4.8 Expiry/Retest Periods An expiry or retest period should be assigned to each excipient and communicated to the customer. Common practice is to use a retest period, rather than an expiry period. 8.3 Control of Nonconforming Product Raw material, intermediate or finished excipient found not to meet its specification should be clearly identified and controlled to prevent inadvertent use or release for sale. A record of nonconforming product should be maintained. Incidences of nonconformance should be investigated to identify the cause. The investigation should be documented and action taken to prevent recurrence. There should be a documented procedure defining how the retrieval of an excipient from distribution should be conducted and recorded. Procedures should exist for the evaluation and subsequent disposition of nonconforming products. Nonconforming product should be reviewed in accordance with documented procedures to determine if it may be: reprocessed/reworked to meet the specified requirements, accepted by the customer with their agreement, re-graded for other applications, destroyed. 8.3.1 Reprocessing Repetition of an activity that is a normal part of the manufacturing process (reprocessing) should only occur when it has already been documented that the excipient may be made in that manner. In all other cases, the guidance for reworking should be followed. Reworking An activity that is not a normal part of the manufacturing process (reworking) should only be conducted following a documented review of risk to excipient
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8.3.2
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APPENDIX A
quality and approval by the quality unit. As appropriate, when performing the risk assessment, consideration should be given to: new impurities that may be introduced as a result of reworking, additional testing to control the reworking, records and traceability to the original batches, suitable acceptance criteria for the reworked excipient, impact on stability or the validity of the re-evaluation interval, performance of the excipient. When the need to rework an excipient is identified an investigation and evaluation of the cause is required. The equivalence of the quality of reworked material to original material should also be evaluated and documented to ensure that the batch will conform to established specifications and characteristics. Batches of excipients that do not conform to specifications individually must not be blended with other batches that do conform in an attempt to hide adulterated or sub-standard material. 8.3.3 Returned Excipients Returned excipients should be identified and quarantined until the quality unit has completed an evaluation of their quality. There should be procedures for holding, testing reprocessing or reworking of the returned excipient. Records for returned products should be maintained and should include the name of the excipient and the batch number, reason for the return, quantity returned and ultimate disposition of the returned excipient.
8.4 Analysis of Data The excipient manufacturer should develop methods for evaluating the effectiveness of its quality management system and use those data to identify opportunities for improvement. Such data can be derived from customer complaints, product reviews, process capability studies, internal and customer audits. The analysis of such data may be used as part of the management review (see also 5.6). A periodic review of key indicators such as product quality attributes, customer complaints and product nonconformities may be conducted to assess the need for improvements. 8.5 Improvement 8.5.1 Continual Improvement The excipient manufacturer should take proactive measures to continuously improve manufacturing and quality management system processes. To identify opportunities for continual improvement, analysis of the following performance indicators may be considered: causes of nonconforming product, results of internal and external audits, customer returns and complaints, process and operational failures.
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APPENDIX A
8.5.2 Corrective Action The excipient manufacturer should establish, document and maintain procedures for: determining the root causes of nonconformities, ensuring that corrective actions are implemented and effective, implementing and recording changes in procedures resulting from corrective action. Preventive Action The excipient manufacturer should establish, document and maintain procedures for: initiating preventive actions to deal with problems at a level corresponding to the risks, implementing and recording changes in procedures resulting from preventive action.
8.5.3
GMP Section Audited Item 8.2 Measurement and Monitoring

8.2.1 Customer Satisfaction 1. Measurements (e.g. complaints, returns, feedback) 8.2.2 Internal Audit 1. Program, conducted; frequency
1. Tracking of measures-complaints, customer assessment of suppliers, etc. 1. Comprehensive GMP audit of quality system operations conducted on a defined periodic basis 2. Written audit reports 3. Details of corrective actions and efficacy 4. Verify measures are taken & effective
2. Audit documentation 3. Corrective measures 4. Verification of corrective actions 8.2.3 Measurement and Monitoring of Processes 1. Measurement of critical process control points 2. Use of appropriate techniques 3. Periodic review and actions 8.2.4 Measurement and Monitoring of Product 1. Documented test methods 2. Fit for purpose 3. Compendial methods used 4. Compendial changes 5. Periodic reviews of product quality 8.2.4.1 Laboratory Controls 1. Procedures and records
1. Adequate monitoring of control points thru testing or measuring device 2. Control techniques effective 3. Review to identify out of trend and impact
1. 2. 3. 4.
Test methods available at test site Methods shown to be suitable Identification of compendial method Monitoring of compendia for change to methods 5. Scheduled review of product quality
1. Procedures available for lab operation and test records are complete: Sample ID Test method reference
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APPENDIX A
Raw data & calculations Test results & specification Analyst signature 2. Labeling and record of preparation and storage to protect integrity
2. Reagents and standards 8.2.4.2 Finished Excipient Testing & Release 1. Quality Unit responsibility 2. Testing instructions 3. Release criteria 4. Continuous processes 8.2.4.3 Out-of-Specification Test Results 1. Procedure, records and actions
1. Documented responsibilities for testing and release 2. Complete instructions to lab technician 3. Released after review of lab, production, and packaging/labeling records 4. Adequate control for continuous processes
1. SOP written and followed: Investigations completed before release or within 30 days SOP guides use of statistical methods and other equipment, methods, lots which might be impacted are investigated 1. SOP specifying quantity, samples retrievable conditions protect retain integrity 2. Specified retention period 1. Lists date of manufacture, site, retest date, etc. (IPEC Guide) 2. COA matches excipient specification 3. Identify skipped test results 1. Developed impurity (i.e. Composition) profile and justify limits are safe 2. If residual solvents are present, limits and test methods on specification 1. Interval based upon experimental data; ongoing 2. Clearly defined and justified 3. Documented program 4. Market container or other (worst case) 5. Parameter(s) monitored to establish interval 6. Stability data reviewed for trend
8.2.4.4 Retained Sample 1. Kept, size and storage
2. Retention period 8.2.4.5 Certificates of Analysis 1. Format and content 2. Alignment to specification 3. Skip lot testing 8.2.4.6 Impurities 1. Defined and controlled 2. Residual solvents 8.2.4.7 Stability 1. Data to support storage conditions 2. Determination of expiry/ reevaluation period 3. Stability program 4. Container type 5. Stability indicating method and parameters 6. Results review & actions 8.2.4.8 Expiration/Re-evaluation Dating
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1. Defined and communicated 1. Expiry or retest duration based on data and on label or COA
8.3 Control of Nonconforming Product Raw material, intermediate or finished excipient found not to meet its specification should be clearly identified and controlled to prevent inadvertent use or release for sale. A record of nonconforming product should be maintained. Incidences of nonconformance should be investigated to identify the cause. The investigation should be documented and action taken to prevent recurrence. There should be a documented procedure defining how the retrieval of an excipient from distribution should be conducted and recorded. Procedures should exist for the evaluation and subsequent disposition of nonconforming products. Nonconforming product should be reviewed in accordance with documented procedures to determine if it may be: reprocessed/reworked to meet the specified requirements, accepted by the customer with their agreement, re-graded for other applications, destroyed. 8.3.3 Reprocessing Repetition of an activity that is a normal part of the manufacturing process (reprocessing) should only occur when it has already been documented that the excipient may be made in that manner. In all other cases, the guidance for reworking should be followed. Reworking An activity that is not a normal part of the manufacturing process (reworking) should only be conducted following a documented review of risk to excipient quality and approval by the quality unit. As appropriate, when performing the risk assessment, consideration should be given to: new impurities that may be introduced as a result of reworking, additional testing to control the reworking, records and traceability to the original batches, suitable acceptance criteria for the reworked excipient, impact on stability or the validity of the re-evaluation interval, performance of the excipient. When the need to rework an excipient is identified an investigation and evaluation of the cause is required. The equivalence of the quality of reworked material to original material should also be evaluated and documented to ensure that the batch will conform to established specifications and characteristics. Batches of excipients that do not conform to specifications individually must not be blended with other batches that do conform in an attempt to hide adulterated or sub-standard material.
8.3.4
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APPENDIX A
8.3.3 Returned Excipients Returned excipients should be identified and quarantined until the quality unit has completed an evaluation of their quality. There should be procedures for holding, testing reprocessing or reworking of the returned excipient. Records for returned products should be maintained and should include the name of the excipient and the batch number, reason for the return, quantity returned and ultimate disposition of the returned excipient.

8.3 Control of Nonconforming Product 1. Procedure and records 2. 3. 4. 8.3.1 Process of retrieval Quarantine Destruction record Reprocessing 1. Reprocessing instructions
1. SOP to determine fate of non-conforming excipient & records 2. Procedure to return from distribution 3. Segregation of off-standard material 4. Timeliness and record of destruction 1. Instructions show how to reprocess and added testing 1. Quality approves written instructions 2. Identify impact on stability, impurities, etc. 1. SOP requires input by Quality and record shows basis for approval 2. Proper identification and segregation
8.3.2 Reworking 1. Rework instructions 2. Excipient quality impact 8.3.3 Returned Excipient Product 1. Procedure and records 2. Identified and quarantined
8.4 Analysis of Data The excipient manufacturer should develop methods for evaluating the effectiveness of its quality management system and use those data to identify opportunities for improvement. Such data can be derived from customer complaints, product reviews, process capability studies, internal and customer audits. The analysis of such data may be used as part of the management review (see also 5.6). A periodic review of key indicators such as product quality attributes, customer complaints and product nonconformities may be conducted to assess the need for improvements.

8.4 Analysis of Data 1. Measures of Quality Management System effectiveness 2. Types of data 3. Periodic reviews
1. System effectiveness is measured 2. Key indicators such as: audits, complaints, first-pass quality, etc 3. Periodic review of these indicators
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APPENDIX A
8.5 Improvement 8.5.1 Continual Improvement The excipient manufacturer should take proactive measures to continuously improve manufacturing and quality management system processes. To identify opportunities for continual improvement, analysis of the following performance indicators may be considered: Root cause identified Measure rectifies deficiency Efficacy is verified results of internal and external audits, customer returns and complaints, process and operational failures. Corrective Action The excipient manufacturer should establish, document and maintain procedures for: determining the root causes of nonconformities, ensuring that corrective actions are implemented and effective, implementing and recording changes in procedures resulting from corrective action. Preventive Action The excipient manufacturer should establish, document and maintain procedures for: initiating preventive actions to deal with problems at a level corresponding to the risks, implementing and recording changes in procedures resulting from preventive action.
8.5.3
8.5.3
GMP Section Audited Item 8.5 Improvement

8.5.1 Continual Improvement 1. Inputs that identify continual improvement opportunities 8.5.2 Corrective Action 1. Root cause analysis 2. Complaints 8.5.3 Preventive Action 1. Risk assessment
1. Investigations as to the cause of returns, complaints, or failures 1. Root cause identified, documented, and reported as appropriate 2. Complaint system documented 1. Risk used to identify need for preventive action
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SOP 8
APPENDIX B Excipient GMP Conformance Assessment

GMP Section Audited Item 4.2 Documentation Requirements 4.2.1 General 4.2.3 Quality Manual 1. Quality Manual Rating
4 QUALITY MANAGEMENT SYSTEMS-EXCIPIENT QUALITY SYSTEMS
2. Quality Policy 3. GMP starting point 4.2.3 Control of Documents 1. Written manufacturing instructions 2. Process fully described 3. Verification of significant steps 4. SOP availability and control
1. Manual is available and reviewed on schedule it describes the quality system and interaction between quality and management processes 2. Policy is deployed 3. Documentation supporting starting point for GMP available (see section 3.2) 1. Document control procedure in place. Documents available and in use 2. Includes all appropriate instructions 3. Verify conformance to process 4. Only current documents are available to operators. Documents impacting quality approved by the quality unit. 5. Scheduled review verified 6. Prevent unauthorized change or approval 1. Written retention policy including storage and policy followed 2. Legible; signed, and dated in ink; errors properly corrected 1. 2. 3. 4. 5. 6. Change Control SOP in place Record and approval of changes Quality review of manufacturing changes Impact assessed by Quality Log (or equivalent) records all changes Change to filing considered, appropriate changes filed, and customers notified as per IPEC Significant Change Guide
5. Periodic review of SOPs 6. Electronic control 4.2.4 Control of Records 1. Record retention SOP 2. Good Documentation Practices 4.3 Change Control 1. Change control procedure 2. Control of production changes 3. Independent approval of changes 4. Impact on qualification and validation 5. Change control log 6. Notification to customers & regulatory
5. . MANAGEMENT RESPONSIBILITY
5.1 Management Commitment 1. Commitment to customer satisfaction 2. Commitment to GMP compliance 5.2 Customer Focus 1. Customer requirements 2. Customer audit policy 1. Quality Policy in place 2. Objectives in place 1. Requirements available to appropriate personnel 2. Audit policy allows at least some audits conducted by customers or their representatives (third party)
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GMP Section Audited Item 5.3 Quality Policy 1. Policy deployment, management support 2. Continual improvement 5.4 Planning 5.4.1 Quality Objectives 1. Conformance objectives 5.4.2 Quality Measurement System Planning 1. Adequate resources Rating
1. Posting, mailing, meetings, etc., and management actions 2. Policy implemented supports continual improvement
1. Written objectives
1. Observation that staffing, equipment, and facilities are sufficient 5.5 Responsibility, Authority and Communication 5.5.1 Responsibility and Authority 1. Reporting relationship of Quality 1. Organizational chart showing Unit and Production independence from production 2. Job descriptions 2. Clear descriptions 3. Clarity of Quality Unit authority 3. Documentation of QA authority and and responsibilities, delegation responsibility 4. Batch release 4. Review of relevant records; confirm who has final authority for release 5.5.2 Management Representative 1. Periodic conformance report to top 1. Management representative appointed and management meetings scheduled to report on quality system conformance to management 5.5.3 Internal Communication 1. Quality system communication 1. Newsletter, email, meetings 2. Top management notification of 2. Evidence of problems reported to top quality critical issues management 5.6 Management Review 5.6.1 General 1. Senior management quality system 1. Documented management reviews review conducted 5.6.2 Review Input 1. Defined 1. Review includes audit findings, process capability, customer complaints, etc. 5.6.3 Review Output 1. Resources and improvements 1. Meeting minutes identifies opportunities identified and need for improvement 6. RESOURCE MANAGEMENT 6.1 Provision of Resources 1. Adequate resources 1. Evidence of sufficient qualified personnel, adequate facilities, space, and equipment 6.2 Human Resources 6.2.1 General 1 Education, training, experience 1. Records, observations and responses 2 Consultant qualifications 2. Qualifications documented
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GMP Section Audited Item 6.2.2 Competence, Awareness and Training 1. Adequate training, experience, & 1. qualifications 2. Training SOP 2. 3. Training program 3. 4. Trainer qualifications 4. 5. GMP training records 5. 6. GMP training frequency 6. 7. Measure of training effectiveness 7. 8. Communicating changing 8. regulations 6.2.3 Personnel Hygiene 1. Personal hygiene training 1. 2. Clothing 3. Reporting of illness 2. 4. Loose items like jewelry and pens 3. 5. Consumption of food, beverage & 4. tobacco products 5. 6. Access control 6. 6.3 Infrastructure (Facilities and Equipment) 6.3.1 Building and Facilities 1. Space 1. 2. Contamination control 2. 3. Toxic products 4. Environmental controls 5. Laboratory facilities 6. State of repair 6.3.2 Equipment 1. Commissioning 2. Maintenance 3. Outdoor equipment 6.3.2.1 Equipment Construction 1. Contact surfaces 2. Lubricants, coolants, etc. 3. Design to minimize contamination 6.3.2.2 Equipment Maintenance 1. Procedures 2. Records 3. Hand over/hand back 6.3.2.3 Computer Systems 1. Access controls
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Rating
Program for training employees; training records and qualifications SOP describing training program Training and content documented Trainer qualifications documented Records of attendance and content Frequency of training in GMPs Appropriate measurements in place Assigned responsibility for monitoring regulations and communicating changes Training program including reporting illness Written gowning requirements Procedure for reporting Observation of loose items Designated areas for consumption Policy on escorting visitors
3. 4. 5. 6.
Evidence of adequate space Protection from environmental contaminants Presence or absence of nearby toxic material or operations Adequate preventive measures Adequate lab facilities Evidence of adequate maintenance
1. Demonstrate suitability for purpose 2. Evidence of proper maintenance 3. No exposure where processing outdoors 1. Unreactive and minimize contamination 2. Use of food grade materials for operating equipment 3. Protect excipient from contamination from personnel 1. SOP for periodic inspection of equipment 2. Records to create equipment use log for critical equipment 3. Return of equipment to service approved and documented 1. Logon ID and Passwords
SOP 8

GMP Section Audited Item 2. Change controls 3. Consistent function 4. Back up, disaster recovery 6.3.3 Utilities 1. Risk of contamination 6.3.4 Water 1. Specification 2. Treatment and monitoring Expected Observation 2. Only authorized changes and log 3. Computer and Software operate as expected 4. Evidence systems are backed up 1. Shown not to contaminate excipient 1. Contact water quality o Potable source or justify 2. DI, DM, RO, & distillation systems require periodic sanitization and maintenance & periodic testing o Quality standard & action limit o Evaluation of poor quality 3. Confirm positive pressure and measures to prevent back flow Rating
3. Positive pressure/back flow
6.4 Work Environment

6.4.1 Air Handling 1. Effectiveness 2. Recirculation 6.4.2 Controlled Environment 1. Required 2. Monitoring 3. Deviations 6.4.3 Cleaning and Sanitary Conditions 1. Appropriately clean 2. Procedures, schedules 3. Waste control 6.4.4 Pest Control 1. Free of infestation 2. Contractor controls 3. Records, review of effectiveness 6.4.5 Lighting 1. Adequate 6.5.6 Drainage 1. Adequate 2. Air break 6.5.7 Washing and Toilet Facilities 1. Adequate facilities 1. Demonstrated efficacy, adequate filters and maintained 2. Documented requirements 1. Temp, humidity, and pressure Specified if control required 2. Evidence the environment is monitored 3. Review of effect on excipient and document 1. Clean and orderly appearance 2. SOP for cleaning and records documenting cleaning 3. Proper storage and removal 1. No signs of infestation 2. Adequate controls in place 3. Controls documented 1. Sufficient lighting with adequate protection (diffuser, screen, etc.) 1. No pooling where excipient exposed 2. Air break or mechanical device in-place 1. Readily accessible with evidence of periodic cleaning and personal hygiene signs 2. Clean with running water, soap, and single use towels or air dryers
SOP 8
2. Clean
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GMP Section Audited Item Rating
7. PRODUCT REALIZATION
7.1 Planning of Product Realization 1. Process flow diagram 2. Critical parameters 3. Batch or continuous 4. Multi-purpose 5. Equipment & lines ID 7.2 Customer-related Processes 7.2.1 Determination of Requirements Related to the Product 1. Customer requirements 2. Agreed additional requirements 7.2.2 Review of Requirements Related to the Product 1. Mutually agreed specifications 2. Contract review 7.2.3 Customer Communication 1. Implementation of customer requirements 2. Notification to customers of significant changes 7.3 Design and Development 1. Technology transfer 7.4 Purchasing 7.4.1 Purchasing Process 1. Qualification and control of suppliers 2. Approved supplier list 3. Audit of key suppliers 4. Selection and control of subcontractors 5. Follow-up of audit corrective actions 6. Material specifications 7. BSE/TSE, etc. risks 7.4.2 Purchasing Information 1. Purchasing agreement 2. Supplier review of specifications 3. Supplier notification of significant change 7.4.3 Verification of Purchased Product 1. Procedures for approval and release 2. Quarantine
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1. 2. 3. 4. 5.
Available Identification and justification Batch identified Other products produced Equipment and lines labeled
1. Procedure for review and approval 2. Identification of other requirements
1. Assure specifications and other requirements are in-place 2. Allow impacted parties to review 1. Prompt incorporation of customer requested change 2. Agreement to notify customers of significant changes 1. Procedure for implementing technology transfer to production
1. SOP for supplier selection and approval 2. Maintenance of list 3. ID of key suppliers and evidence of audits 4. SOP for subcontractor assessment and oversight 5. Track audit corrective actions 6. Written raw material specifications 7. Acknowledgement of animal sourced materials, allergens, etc. 1. Written agreement 2. Acknowledgement specifications are approved 3. Written agreement to notify of significant change 1. Approval includes QC and confirmation of COA 2. Quarantine appropriate & maintained
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GMP Section Audited Item Expected Observation 3. Sampling procedures and 3. Conducted with a defined plan under conditions appropriate conditions 4. Testing/verification 4. Adequate samples taken and tested 5. Bulk deliveries 5. Dedicated or certified clean vehicles 7.5 Production and Service Provision 7.5.1 Control of Production and Service Provision 7.5.1.1 Production Instructions and Records 1. Controlled master batch 1. Controlled document instructions 2. Retrievable batch records 2. Proper storage and retrieval of records 3. Suitable details 3. Record shows instructions were followed 7.5.1.2 Equipment Cleaning 1. Dedicated or controls for 1. Measures to prevent cross-contamination cross-contamination 2. Cleaning effectiveness and 2. Evidence of effectiveness of cleaning justification 3. Documentation of cleaning 3. Records show sequence of cleaning and use 4. Storage of utensils and 4. Utensil storage protects from sampling devices environmental contamination 5. Continuous processes, 5. Frequency of cleaning justified frequency of cleaning 7.5.1.3 Recovery of Solvents 1. Controls in place 1. Specification in place and recovered solvent is tested, including continuous processes 2. Traceability 2. Adequate records for mother liquors and filtrates 7.5.1.4 In-Process Blending/Mixing 1. Blending procedures 1. Complete instructions 2. Defined blending parameters 2. Blending parameters or spec to confirm quality of blend 3. Part containers/tails 3. Fate of short containers or tailings 7.5.1.5 In-Process Control 1. Program 1. Instructions with set-points, limits 2. Sampling procedures 2. Clear, appropriate instructions 3. Results recorded 3. Records show conformance 4. Control actions 4. Instructions how to control process and SOP when material fails 7.5.1.6 Packaging and Labeling 1. Procedures 1. SOP includes confirming area is clear and ready for packaging 2. Label control 2. Security to prevent misuse 3. Mix-up prevention 3. Measures to assure correct label is used 7.5.1.7 Records of Equipment Use 1. Sequence of activities 1. Production, maintenance, cleaning sequence documented in equipment log or
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Rating

GMP Section Audited Item 7.5.2 Validation of Processes for Production and Service Provision 1. Process consistency 7.5.3 Identification and Traceability 7.5.3.1 Traceability 1. Material to their manufacturer 2. Material through production 3. Unique batch numbering 4. Batch definition for continuous processing 5. Traceability of reprocessed material 6. Origin of manufacturing site 7.5.3.2 Inspection & Test Status 1. Approval of materials & packaging 2. Controls for unapproved materials 3. Identification of containers and equipment 4. Status identification 5. Identification of unlabeled container 6. Evaluation of raw materials beyond expiration or use date 7. Quarantine control 7.5.3.3 Labeling 1. Excipient labeling content 2. Special storage condition labeling 7.5.4 Customer Property 1. Procedure 2. Agreements for confidential information 7.5.5 Preservation of Product 7.5.5.1 Handling, Storage, and Preservation 1. Appropriate conditions and record 2. Outside storage 3. Bulk storage dispensing
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Expected Observation equivalent records
Rating
1. Process demonstrated to be capable
1. Records show source of material 2. Material lot ID part of production record 3. Batch clearly defined with unique excipient lot number 4. Definition of batch 5. Adequate records 6. Identification of site of manufacture 1. QC approval 2. Physical segregation or computer control to prevent use 3. All equipment and containers identified 4. Identification of status thru labels or computer system 5. Information to ID content of unlabeled containers 6. SOP for evaluation of raw materials beyond expiration or use date and Quality approval 7. Adequate physical separation, status labels or computer system 1. Name, grade, quantity, lot number and manufacturer 2. If needed on label including expiry date
1. Controls to prevent use in other than intended customers product(s) 2. Confidentiality maintained
1. Documentation of conditions where specified 2. Protection of package & label 3. Procedures in place to assure dispensing
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GMP Section Audited Item Expected Observation systems are accurate and to prevent shipment of unreleased excipient 4. Procedures to assure FIFO 1. Documented study showing packaging protects excipient 2. Packaging stored to prevent deterioration 3. Validation of container cleaning and label removal 4. Documentation of cleanliness and prior load 5. All openings sealed 6. Package seal would show tampering 1. Adequate shipping records 2. Verifiable documentation 3. Procedure and periodic test to demonstrate effectiveness Rating
4. Stock rotation 7.5.5.2 Packaging Systems 1. Adequate protection to excipient 2. Storage of packaging components 3. Reusable packaging 4. Bulk container cleanliness 5. Bulk container seals 6. Tamper evident Seals 7.5.5.3 Delivery and Distribution 1. Distribution records 2. Traceable to consignee 3. Retrieval or market withdrawal procedure 7.6 Control of Measuring and Monitoring Devices 1. Calibration procedures, records, and status 2. Standards-handling and storage
1. SOP describes all activities 2. Stored and handled in-house to prevent deterioration and traceable to a national standard 3. Established calibration frequency and limits, and removal from service if out of calibration or beyond due date 4. Actions to take if out of calibration
3. Frequency and limits
4. Out of calibration actions 8.1 General 1. Quality management processes
8. MEASUREMENT, ANALYSIS AND IMPROVEMENT

1. Monitoring and measuring activities including excipient quality
8.2 Measurement and Monitoring

8.2.1 Customer Satisfaction 1. Measurements (e.g. complaints, returns, feedback) 8.2.2 Internal Audit 1. Program, conducted; frequency 1. Tracking of measures-complaints, customer assessment of suppliers, etc. 1. Comprehensive GMP audit of quality system operations conducted on a defined periodic basis 2. Written audit reports 3. Details of corrective actions and efficacy 4. Verify measures are taken & effective
2. Audit documentation 3. Corrective measures 4. Verification of corrective actions
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SOP 8

GMP Section Audited Item 8.2.3 Measurement and Monitoring of Processes 1. Measurement of critical process control points 2. Use of appropriate techniques 3. Periodic review and actions 8.2.4 Measurement and Monitoring of Product 1. Documented test methods 2. Fit for purpose 3. Compendial methods used 4. Compendial changes 5. Periodic reviews of product quality 8.2.4.1 Laboratory Controls 1. Procedures and records Rating
1. Adequate monitoring of control points thru testing or measuring device 2. Control techniques effective 3. Review to identify out of trend and impact
1. 2. 3. 4.
Test methods available at test site Methods shown to be suitable Identification of compendial method Monitoring of compendia for change to methods 5. Scheduled review of product quality 1. Procedures available for lab operation and test records are complete: Sample ID Test method reference Raw data & calculations Test results & specification Analyst signature 2. Labeling and record of preparation and storage to protect integrity
2. Reagents and standards 8.2.4.2 Finished Excipient Testing & Release 1. Quality Unit responsibility 2. Testing instructions 3. Release criteria 4. Continuous processes 8.2.4.3 Out-of-Specification Test Results 1. Procedure, records and actions
1. Documented responsibilities for testing and release 2. Complete instructions to lab technician 3. Released after review of lab, production, and packaging/labeling records 4. Adequate control for continuous processes
1. SOP written and followed: Investigations completed before release or within 30 days SOP guides use of statistical methods and other equipment, methods, lots which might be impacted are investigated 1. SOP specifying quantity, samples retrievable conditions protect retain integrity 2. Specified retention period
8.2.4.4 Retained Sample 1. Kept, size and storage
2. Retention period 8.2.4.5 Certificates of Analysis

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SOP 8

GMP Section Audited Item 1. Format and content 2. Alignment to specification 3. Skip lot testing 8.2.4.6 Impurities 1. Defined and controlled 2. Residual solvents 8.2.4.7 Stability 1. Data to support storage conditions 2. Determination of expiry/ reevaluation period 3. Stability program 4. Container type 5. Stability indicating method and parameters 6. Results review & actions 8.2.4.8 Expiration/Re-evaluation Dating 1. Defined and communicated 8.3 Control of Nonconforming Product 1. Procedure and records 2. Process of retrieval 3. Quarantine 4. Destruction record 8.3.1 Reprocessing 1. Reprocessing instructions 8.3.2 Reworking 1. Rework instructions 2. Excipient quality impact 8.3.3 Returned Excipient Product 1. Procedure and records 2. Identified and quarantined 8.4 Analysis of Data 1. Measures of Quality Management System effectiveness 2. Types of data 3. Periodic reviews Expected Observation 1. Lists date of manufacture, site, retest date, etc. (IPEC Guide) 2. COA matches excipient specification 3. Identify skipped test results 1. Developed impurity (i.e. Composition) profile and justify limits are safe 2. If residual solvents are present, limits and test methods on specification 1. Interval based upon experimental data; ongoing 2. Clearly defined and justified 3. Documented program 4. Market container or other (worst case) 5. Parameter(s) monitored to establish interval 6. Stability data reviewed for trend Rating
1. Expiry or retest duration based on data and on label or COA 1. SOP to determine fate of non-conforming excipient & records 2. Procedure to return from distribution 3. Segregation of off-standard material 4. Timeliness and record of destruction 1. Instructions show how to reprocess and added testing 1. Quality approves written instructions 2. Identify impact on stability, impurities, etc. 1. SOP requires input by Quality and record shows basis for approval 2. Proper identification and segregation 1. System effectiveness is measured 2. Key indicators such as: audits, complaints, first-pass quality, etc 3. Periodic review of these indicators
8.5 Improvement
8.5.1 Continual Improvement 1. Inputs that identify continual improvement opportunities
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1. Investigations as to the cause of returns, complaints, or failures

SOP 8

GMP Section Audited Item 8.5.2 Corrective Action 1. Root cause analysis 2. Complaints 8.5.3 Preventive Action 1. Risk assessment Rating
1. Root cause identified, documented, and reported as appropriate 2. Complaint system documented 1. Risk used to identify need for preventive action
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SOP 8

SOP 08-IPEA Certification Criteria Rev 2

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STANDARD OPERATING PROCEDURE

International Pharmaceutical Excipients Auditing, Inc.

IPEA Management Committee

Feb. 17, 2011

STANDARD OPERATING PROCEDURE

IPEA Management Committee

Feb. 17, 2011

STANDARD OPERATING PROCEDURE

IPEA Management Committee

Feb. 17, 2011

Effective Date Dec 15, 2008 Aug. 28, 2009

STANDARD OPERATING PROCEDURE

IPEA Management Committee

Feb. 17, 2011

Feb. 17, 2011

Substantially Meets (SM)

Partially Meets (PM)

4 QUALITY MANAGEMENT SYSTEM- EXCIPIENT QUALITY SYSTEMS

4 QUALITY MANAGEMENT SYSTEMS-EXCIPIENT QUALITY SYSTEMS

GMP Section Audited Item

APPENDIX A 5 MANAGEMENT RESPONSIBILITY

GMP Section Audited Item 5. . MANAGEMENT RESPONSIBILITY

1. Quality Policy in place 2. Objectives in place

GMP Section Audited Item

GMP Section Audited Item

GMP Section Audited Item

1. Observation that staffing, equipment and facilities are sufficient

GMP Section Audited Item

GMP Section Audited Item

GMP Section Audited Item 6. RESOURCE MANAGEMENT

Rating Expected Observation

1. Evidence of sufficient qualified personnel, adequate facilities, space, and equipment

GMP Section Audited Item

Rating Expected Observation

1. Records, observations and responses 2. Qualifications documented

GMP Section Audited Item

Rating Expected Observation

3. Positive pressure/back flow

GMP Section Audited Item 6.4 Work Environment

Rating Expected Observation

GMP Section Audited Item 7. PRODUCT REALIZATION

Rating Expected Observation

GMP Section Audited Item

Rating Expected Observation

GMP Section Audited Item

Rating Expected Observation

1. Procedure for implementing technology transfer to production

GMP Section Audited Item

Rating Expected Observation

APPENDIX A GMP Section Audited Item Rating Expected Observation

GMP Section Audited Item

Rating Expected Observation

1. Process demonstrated to be capable

GMP Section Audited Item

Rating Expected Observation

GMP Section Audited Item

Rating Expected Observation

GMP Section Audited Item

Rating Expected Observation

GMP Section Audited Item