g Sop 011005

GLOBAL STANDARD OPERATING PROCEDURENumber

GSOP-011-005

Division: GLOBAL QUALITYPage

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Title: ANNUAL PRODUCT QUALITY REVIEWS

1.0 Purpose

1.1 To establish a harmonized procedure for conducting Annual Product Quality Reviews of all

pharmaceutical products per the applicable regulatory requirements.

2.0 Scope

2.1 This Global SOP applies to the Apotex group of companies producing finished dosage forms, as

applicable to companys operation(s).

2.2 This Global SOP may be used for the assessment and oversight of Apotex Third Party Organizations.

2.3 This Global SOP establishes what shall be achieved by all parties planning for and carrying out Annual

Product Reviews in compliance with the regulatory requirements.

2.4 In some cases this Global SOP may address regulations and/or activities that do not apply to the

Site/Centralized Functional area operations. Each Site/Centralized Function shall justify non-applicability

during assessment and implementation of this Global SOP.

2.5 Where needed and justified, a Site/Centralized Function may create/revise a site-specific/centralized

function SOP on the subject of this Global SOP. The site-specific/centralized function SOP must not

contradict the requirements in this Global SOP and shall fulfill the requirements of this Global SOP, as

applicable to site/centralized function operations.

3.0 Owner Organizational Unit

AGO-QA-Global Policy and Systems

4.0 General Training Requirements

4.1 The following individuals of all Global, Corporate and Centralized functional areas (Quality, Compliance,

Legal, Drug Safety and Pharmacovigilance, Manufacturing Operations, Research and Development,

Engineering Services, Product Development and Technical Operations, Warehouse and Distribution and

Finance, etc.) must be trained on this Global SOP:

- Executive Management and members of the EOC

- Directors

- Senior Managers

4.2 Site Quality Heads must be trained on this Global SOP, if applicable to Site Operations.

GSOP-011-005 rev. 1 Effective Date: 09/05/2014 Page incl. Approval: 1 of 21

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4.3 Training of other Site/Centralized function personnel on the applicable requirements of this Global SOP

shall take place during site implementation of this Global SOP. This training will be executed on the

Site/Centralized function level SOP(s).

5.0 Associated Documents

Document # Document Title Relationship

GQM Global Quality Manual Governing Quality Manual

GPOL-002 Management Controls Governance,

Management Notification, Management

Review

Associated Global Policy

GPOL-007 Manufacturing, Packaging and Labelling

Controls


GPOL-009 GMP Document Controls and Records

Management


GPOL-011 Regulatory Program Associated Global Policy

GPOL-014 Quality Risk Management Associated Global Policy

GPOL-017 Failure and Deviation Investigation

Management


GPOL-021 Corrective and Preventive Action (CAPA) Associated Global Policy

GSOP-026-002 Product Recall and Market Action Associated Global Standard

Operating Procedure

GSOP-026-003 Regulatory Notification Associated Global Standard

Operating Procedure

6.0 Exhibits

Exhibit Title

Exhibit A Annual Product Quality Review Process Overview

Exhibit B Annual Product Quality Review Relationship to the Quality System


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7.0 Definitions

Term Definition

Apotex Apotex group of companies producing finished dosage forms. Term also

includes the affiliates and distribution centers.

Corrective and Preventive

Action

A systematic approach that includes actions needed to correct (correction), avoid

recurrence (corrective action) and eliminate the cause of potential

nonconforming product and other quality problems (preventive action).

Out-of-Specification (OOS) Any examination, measurement or test value that does not conform to pre-

established criteria.

Out-of-Trend (OOT) Any analytical result that is within specification but is inconsistent with previously

determined results for the same material or similar results for similar materials.

For example, an in-specification result that is atypical outside the control limits

for the test.

Risk Assessment Determination of criticality based upon consideration of, but not limited to, the

following factors:

1. Compliance (QA/RA) Impact regulatory implications

2. Safety Risk (PV) risk to human life (considering severity, occurrences, etc.)

3. Distribution Pattern location of affected batches

4. Speed to initiate action

Third Party Manufacturer A universal term applied to a company under contract to manufacture products

distributed by Apotex. This would include the following:

- Contract Manufacturer/Packager a company under contract to manufacture

and/or package Apotex-owned products.

- Private Label Manufacturer a company who manufactures their products for

Apotex with an Apotex label.

- Joint Venture Manufacturer a company, who manufactures products for

Apotex that is jointly developed, owned and or marketed with Apotex.

Third Party Contractor

(TPC)

Any external entity manufacturing active pharmaceutical ingredient (API), bulk or

finished Apotex products.

- Any external entity responsible for packaging or repackaging bulk or finished

products (e.g. packagers, warehouses, distributors)

- Any contract analysis organization (including laboratory involved in testing of

APIs, API starting materials, bulk and finished Apotex products, development of

analytical testing methods, local retesting and execution of follow-up stability

studies)


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8.0 Process Overview

See Process Overview in Exhibit A.

9.0 Roles and Responsibilities

Role Responsibility

EVP,

Global Supply Operations

- Review and Approve this Global SOP

- Ensure the Deployment / Implementation of this Global SOP at

applicable Global Apotex sites

Executive Vice President,

Global R&D

- Review and Approve this Global SOP

- Ensure the Deployment / Implementation of this Global SOP within

Global R&D functions

Senior VP,

Scientific & Regulatory Affairs

- Review and approve this Global SOP


Scientific & Regulatory Affairs functions

Global Director,

R&D QA

- Review this Global SOP


R&D QA functions

Global Director,

External Quality


Global Director,

QA Audit


VP,

Global Quality Manufacturing

Sites


- Ensure the Deployment / Implementation of this Global SOP at

applicable Manufacturing sites

Global Director,

Quality Compliance



Global Compliance functions

Global Director, QA Policy and

Systems- Review and Approve this Global SOP

- Oversee the Management, Review, Approval, and Deployment /

Implementation of this Global SOP at applicable Global Apotex sites


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Role Responsibility

QA Global Policy and Systems

Department- Issue, review and revise this Global SOP according to current Health

Authority regulation and guidance

- Distribute this Global SOP

- Orchestrate the Deployment / Implementation of this Global SOP at

applicable Global Apotex sites

Site Leadership Team

(Site Operations Head,

Site Quality Head)

- Support Deployment / Implementation of this Global SOP at applicable

Global Apotex sites

- Coordinate Annual Product Quality Review activities across

interdisciplinary teams and departments at the site

- Ensure that Annual Product Quality Review processes are defined,

deployed and reviewed, and that adequate resources are available at

the site

10.0 General Requirements US Market

10.1 Apotex shall ensure that written records are maintained so that data therein can be used for evaluating,

annually (at minimum), the quality standards of each drug product to determine the need for changes in

drug product specifications, manufacturing or control procedures [CFR 211.180(e)]. This written

procedure establishes the process for such evaluations including provisions for:

- A review of a representative number of batches, whether approved or rejected and, where applicable,

records associated with the batch.

- A review of complaints recalls and returned drug products, and investigations conducted under CFR

211.192 for each drug product.

11.0 General Requirements - Health Canada

11.1 Regular periodic or rolling quality reviews of all drugs should be conducted with the objective of verifying

the consistency of the existing process, the appropriateness of current specifications for both raw

materials and finished product to highlight any trends and to identify product and process improvements.

Such reviews should normally be conducted and documented annually, taking into account previous

reviews, and should include, at minimum, a review of:

- Critical in-process controls, finished product testing results and specifications.

- All batches that failed to meet established specification(s) and their investigation.

- All significant deviations or non-conformances, their related investigations, and the effectiveness of

resultant Corrective and Preventive Actions (CAPA) taken.

- All changes carried out to the processes, analytical methods, raw materials, packaging materials, or

critical suppliers.


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- The results of the continuing stability program and any adverse trends.

- All quality-related returns, complaints and recalls and the investigations performed at the time.

- Adequacy of any previous corrective actions related to product process, or equipment.

- The qualification status of relevant equipment and systems (e.g. HVAC, water, compressed gases,

etc.); and

- Agreements to ensure that they are up to date.

Note: Quality reviews may be grouped by product type (e.g. solid dosage forms, liquid

dosage forms, sterile products, etc. where scientifically justified).

11.2 The Quality Assurance/ Control department of the importer or distributor should ensure that the annual

product quality review is performed in a timely manner.

11.3 Where required, there should be an agreement in place between the various parties involved (e.g.

importer and fabricator) that defines their respective responsibilities in producing and assessing the

Quality review and taking any subsequent CAPAs.

11.4 The Quality Assurance/Control department should evaluate the results of this review and an assessment

should be made whether CAPAs or any revalidation should be undertaken. Reasons for such corrective

actions should be documented. Agreed upon CAPAs should be completed in a timely and effective

manner. There should be procedures for the ongoing management and review of these actions and the

effectiveness of these procedures verified during self-inspection.

12.0 General Requirements European Market and PIC/s Countries

12.1 Apotex shall ensure that regular periodic or rolling quality reviews of all licensed medicinal products,

including export only products, are conducted with the objective of verifying the consistency of the

existing process, the appropriateness of current specifications for both starting materials and finished

product. Such reviews shall normally be conducted and documented annually taking into account

previous reviews, and shall include, at minimum, a review of:

- Starting materials and packaging material used for the product especially those from new sources.

- Critical in-process controls and finished product results.

- All batches that failed to meet established specification and their investigations.

- All significant deviations or non-conformances, their related investigations, and the effectiveness of

resultant CAPAs taken.

- All changes carried out to the process or analytical methods.

- Marketing Authorization variations submitted / granted / refused.

- The results of the stability monitoring program and any adverse trends.

- All quality related returns, complaints, recalls and investigations performed at the time.

- Adequacy of any other previous product process or equipment corrective actions.


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- Post-marketing commitments for new marketing authorizations and variations to marketing

authorizations.

- The qualification status of relevant equipment and utilities (e.g. HVAC, water, compressed gases

etc.).

- Technical Agreements to ensure that they are up to date.

12.2 The manufacturer and marketing authorization holder, where different shall evaluate the results of this

review and an assessment shall be made whether CAPA(s) or any revalidation shall be undertaken.

12.2.1 Reasons for such corrective actions shall be documented.

12.2.2 CAPAs shall be completed in a timely and effective manner. There shall be management

procedures for on-going management and review of these actions and the effectiveness of

these procedures verified during self-inspections. Product Reviews may be grouped by product

type (e.g. solid dosage forms, liquid dosage forms, sterile product, etc.) where scientifically

justified.

12.3 Where the marketing authorization holder is not the manufacturer, there shall be a Technical Agreement

in place between the various parties that defines their respective responsibilities in producing the product

quality review. The Qualified Person responsible for final batch certification together with the marketing

authorization holder shall ensure that the product review is performed in a timely and accurate manner.

13.0 Apotex Third Party Department Responsibilities:

13.1 In coordination with the Third Party Manufacturer), determine schedule of APR/PQR quality review

annually and communicate the schedule to the appropriate contractors / Apotex groups.

13.2 Receive and review the reports as provided from the Third Party Manufacturer sites and require any

necessary changes / corrections / additional information.

13.3 Work closely with the Data Contributors, responsible to prepare the sections not submitted by the Third

Party Manufacturer; assure that the format and content of the sections are as required in order to

complete the report. These may include sections such as Stability Assessment, Regulatory Assessment,

Technical Complaints, Medical Assessments, etc.

13.4 Collect, review and analyze data elements to provide an assessment of the process / product and make

recommendations for continuous improvement.

13.5 Review and approve the final report within the established timeframes.

13.6 Communicate overdue reports (or soon to be overdue reports) to Apotex-Management.

13.7 Provide risk assessment when required for product that is to be released during the time that the

APR/PQR review is overdue. Strong rationale must be provided to the Vice President, Global Quality and

Compliance.


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13.8 Ensure CAPAs defined in the outcome of the APR/PQR review are implemented at the Third Party

Manufacturer or by Apotex as appropriate. CAPA should be recorded and tracked.

13.9 Monitor implementation of the CAPAs defined in outcome of the APR/PQR and evaluate the effectiveness

of CAPA in the next annual review period.

13.10 Archive the final approved report in accordance with the local record retention requirements and the

related procedures

14.0 Annual Product Quality Review Responsibilities

14.1 Any Apotex site supplying intermediate or bulk product to another site must perform an annual scheduled

review of the supplied product.

14.2 The site filling the primary containers used for marketing must perform a product review. It must use the

results of any intermediate or bulk product supplying site review as part of the product review for which it

is responsible.

14.3 Sites or companies that carry out secondary packaging of filled primary containers, or import finished

products, must review the conformance of supplying site data to local market regulations.

14.4 Site Quality Head is responsible for:

- Overall coordination of Annual Product Quality Review and shall identify a representative(s) from the

Quality Assurance (QA) group for overall scheduling and management.

- Ensuring that the Annual Product Quality Review is completed on time.

- Overseeing the applicable processes listed in the SOP.

- Ensuring investigations when adverse trends are observed during the Annual Product Quality

Reviews.

- Reviewing and Approving the Annual Product Quality Review Summary Report:

Ensures a change record is created and agreeing with the recommended change(s).

Ensuring commitments for changes and improvements are tracked and completed

through the CAPA system.

14.5 Operations, Technical Services and QA are responsible for:

- Batch Record Review including In-process controls

- Review of Rework, reprocessing, and reject information

- Review of yields, deviations and product investigations

- Process Validation Review

- Product / Process related changes

- Effectiveness of Corrective Actions (close outs)


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- Follow-up from previous Annual Product Quality Review reports

- Significant product related deviations and incidents

14.6 Quality Control Laboratory and QA Heads are responsible for:

- Review of Quality Control Test results including out-of-specification events, non-conformances and

associated Laboratory Investigation Reports (LIR)

- Finished product specification review and change history

- Changes to Analytical Methods and Test Method Validation

- Stability Data and program review

- Retention Sample program review

15.0 Product Grouping Strategy (Except for US Products)

15.1 With the exception of the US products, grouping products by a particular characteristic/type is acceptable.

The grouping strategy must be applied with caution and using the following justification criteria examples:

- Common dose forms (sterile products, orals solutions, solid dosage, oral powders etc.)

- Common container closure formats different container sizes may be grouped (e.g. 20 mL and 25

mL of the same presentation).

- Different strength may be grouped if they are in the same container closure system

(e.g. 50 mg/100 mL and 100 mg/100 mL).

- Common APIs within a dose form.

- Products with substantially equivalent processing steps.

- Products with substantially equivalent excipient/carrier bases (e.g. oily versus aqueous preparations).

- Note: Products with different market authorization shall not be grouped together (e.g. OTC and

prescription) Grouping shall be justified in writing with the criteria used.

16.0 Scheduling

16.1 The periodic quality review for all Apotex products is to be performed annually based on a twelve month

review period. The responsible QA/APR/PQR Manager will generate the annual product review schedule

by the first of November of each year for the following calendar year.

16.2 All parties will mutually agree to an APR/PQR review reporting schedule by the end of November. The

schedule must include a timeline that allows for the completion of the review process so that it is not

longer than 90 days past the end of the 12 month data review period for Apotex products or not longer

than 120 days past the end of the 12 month data review period for Third Party manufactured products.

Typically, 30 days prior to the APR/PQR due date should be reserved to obtain approvals.

16.3 The agreed upon annual product quality schedule will be submitted to QA for formal approval.


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16.4 The approved product review schedule is a GMP document and should be maintained in the local

document management system with a requirement for retention as defined by global document retention

procedure.

16.5 Periodic status reports will be submitted to the appropriate site management team detailing the

compliance to the annual process.

17.0 Procedure

Note: Refer to Exhibit B for establishment of the relationship between the Annual Product Quality Review and

the Quality System.

17.1 An Annual Product Quality Review shall be compiled based on the approval date of the product. The

approved Annual Product Quality Review shall be available within 90 business days after the end of the

review period.

17.2 A cross-functional team based approach shall be used. While the overall coordination and preparation of

the Annual Product Quality Review dossier will reside with Site Quality Head, the individual section

preparation must be completed by the Subject Matter Experts in the respective departments as defined in

the responsibilities section of this procedure.

17.3 All batches of all the commercial products manufactured, packed and distributed during the review period

shall be included in the evaluation.

17.4 Along with the Annual Product Quality Review, implementation of previous years recommendations shall

be reviewed.

17.5 Site Quality Head or designee shall arrange a meeting with the concerned Department Heads to finalize

the action plan, responsibilities and deliverables (if any), based on the recommendations made in the

Conclusion section of the Annual Product Quality Review.

17.6 Site Quality Head or authorized designee shall approve the Annual Product Quality Review.

17.7 Details of any CAPAs (as required), shall be forwarded to the concerned Department Heads for

necessary actions.

17.8 Manager, QA or designee shall follow-up on the corrective action to ensure compliance of the comments /

recommendations.

17.9 The complete and approved Annual Product Quality Review shall be maintained by Quality Assurance as

per the retention period specified within applicable Global Policy [GPOL-009 - GMP Document Controls

and Records Management] and site procedures.

17.10 For products distributed in Europe, an electronic copy of the approved Annual Product Quality Review

(preferably in .pdf format) shall be shared with the Qualified Person at Apotex Netherlands within 30

business days from completion.


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17.11 Products that are discontinued will be periodically reviewed through the expiration date of the last batch

manufactured or the end of the stability study, whichever is longer.

18.0 Annual Product Quality Reviews Report Format

18.1 The Annual Product Quality Review report package must include (at minimum) the following information

and sections:

- Cover Page: Including Name of the product, Strength, Review Period, Market and Manufacturing

site.

- Summary Section

- Table of Contents

- Executive Summary Report: This shall include a section by section summary of the entire review,

along with a synopsis of any comments or concerns made in the individual section. It shall also

include a conclusion and rating identifying the corresponding action (Refer to Table 1).

Table 1: Conclusion Rating and Action

Rating Action

Acceptable No Risk assessment is warranted.

Acceptable with conditions Risk assessment shall be performed.

Unacceptable A risk assessment is warranted, and notification to

Regulatory Agencies shall be considered as a part of

mitigation and communication.

18.1.1 Batch Record Review

18.1.1.1 This section covers the results of the batch record review and a list of Batches

Released for commercial distribution, rejected / failed batches that failed to meet

established specifications.

18.1.1.2 Confirm that all batch records for commercial product have been reviewed as per the

Disposition process, including all batch records for rejected batches.

18.1.1.3 Where information is available via validated ERP system, batch disposition can be

retrieved electronically.

18.1.2 Starting Material and API Reviews

18.1.2.1 This section includes the review of API, excipients and primary packaging materials

used in the product. Also includes the API batches released and rejected / failed

during the review period. Trend analysis of API, excipients and primary packing

materials shall be part of this section as well as any changes to the suppliers.

18.1.3 Process Control Review

18.1.3.1 This section covers the review of critical in-process controls (In-process and finished

product acceptable quality levels). The results obtained shall be compared with the

standard values / range. For each batch, compile the percentage yield obtained at all

critical stages.


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18.1.4 Laboratory Test Results and Trends

18.1.4.1 This section evaluates the analytical test results of finished products and in-process

data of all relevant critical parameters including trend analysis of these critical

parameters.

18.1.5 Laboratory Out-of-Specification (OOS) and CAPA

18.1.5.1 This section summarizes all deviations, incidents, notifications, OOS, Out-of-Trend

(OOT), LIR, AQRS (CAPA, Investigation and Excursion) and related detailed

investigations including the effectiveness of CAPAs executed.

18.1.6 Change Control Review

18.1.6.1 This section covers the summary of any changes carried out to the product, process

(manufacturing, packaging, labelling and specification), system or methods specific to

the product.

18.1.7 Validation Review

18.1.7.1 This section summarizes the validation study details of manufacturing process

(completed and on-going process validation studies).

18.1.8 Facilities and Equipment Review (Product Specific)

18.1.8.1 This section reviews the qualification status of equipment and utilities (e.g. HVAC,

Water, compressed air etc.). This section also covers the review of the Qualification

status of new / existing and re-qualification of the equipment and utilities.

18.1.9 Specifications Review

Note: This section is applicable only to the sites that do not have established regular

Compendia review program.

18.1.9.1 Material and Product Specification Review

18.1.9.1.1 This section covers the review of current specifications (API, In-process,

stability and finished product) to be in line with the approved

manufacturing documentation.

18.1.9.1.2 Summarize the results of the verification and highlight any gaps.

18.1.9.2 Compendia Specification Review

18.1.9.2.1 This section covers the review of current specifications (API, In-process,

stability and finished product) with respect to appropriate product

monograph.

18.1.9.2.2 Summarize the results of the verification and highlight any gaps.

18.1.10 Customer Complaints Review

18.1.10.1 This section summarizes the market complaint investigation and planned

CAPAs.

18.1.11 Medical Complaints (Adverse Events)

18.1.11.1 Drug Safety / Pharmacovigilance shall include in their assessment report input

on Adverse Events with possible technical background. This should be

available for the Apr/PQR technical writer.


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18.1.11.2 Manufacturing sites that include this information as part of their complaint trend

report do not need to include this within the APR/PQR, but must provide the

appropriate link to the information.

18.1.12 Regulatory Actions Review

18.1.12.1 This section covers the field alerts, product recalls and returned goods (if any).

Also includes, reasons and corrective actions planned.

18.1.13 Marketing Authorization Variations and Post-Marketing Commitments

18.1.13.1 Regulatory team shall provide a summary of the marketing authorization

variations submitted, granted, or refused during the reporting period, the filed

document reference, and post-marketing commitments for markets as

applicable, as per the local GMP requirements for those markets e.g. EU and

Aus require a summary of variations and commitments. Include the report as

an attachment to the APR/PQR.

18.1.14 Returned Products

18.1.14.1 Gather information for all returned products related to quality issues which

occurred during the review period; including the reason for return.

18.1.14.2 Using the table in the APR/PQR report, provide the following information:

- Type - Issue Category (Product Returned)

- Number of actions

- Associated batch numbers

- Trend (Yes/No)

- Comments and/or corrective actions taken

18.1.14.3 If investigations were initiated, the results and the decision on the final use

should also be listed.

18.1.14.4 Any products that were returned as a result of a customer complaint should

also be evaluated.

18.1.15 Technical Agreements

18.1.15.1 This section reviews the technical agreements between Apotex and the third

party manufacturer or contractor to ensure that they are up to date (as

applicable).

18.1.16 Retention Sample Program Review

18.1.16.1 This section covers the retention sample review of the product.

18.1.16.2 Sites shall have site specific SOP for the collection, storage, retrieval; review

and disposition of reserved/control samples for drug products with delineation

of retention period(s) and visual inspection requirements.

18.1.16.3 Visual inspection with the opening of the primary packaging shall be performed

at least once a year against visual appearance specifications.


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18.1.17 External Manufacturing / Testing Services Review

18.1.17.1 Review of the Third Party Manufacturers APQR (if any) and the comment /

suggestions will be included in this section. Comments / Suggestions (if any)

will be forwarded to the Third Party manufacturer by the External

Manufacturing Quality group.

18.1.18 Stability Program

18.1.18.1 This section covers the review of results of the stability monitoring program

including the available raw data for stability and references to full stability

reports.

18.1.19 Review of Previous Annual Product Quality Review

18.1.19.1 The Technical Writer or data contributor (as appropriate) will obtain a copy of

the previous APR/PQR.

18.1.19.2 The report will be reviewed to determine whether there were any actions and/or

recommendations that should be considered for the current review period. The

reviewer will determine the status of the recommended actions and include the

information pertaining to recommendations and status of actions in the relevant

section of the report.

18.1.20 Recommendations and Conclusions

18.1.20.1 Include any recommendations generated during the review and analysis of the

data. During the review process, any changes, additional information or

corrections will be communicated to the author of the section or to the Third

Party contractor or manufacturer as applicable. The holistic review will be

completed once all sections are deemed appropriate.

18.1.20.2 The authors are to provide specific statements (as applicable to their section)

on the compliance and validation status and include any new knowledge

gained during the review process and defining corrective actions to be taken to

remediate any issues observed.

18.1.20.3 The executive summary will be generated by QA following the holistic review

and will include the necessary detail to assess the current status of the product

with the recommendations as noted above for any areas of improvement or

concern.

18.1.20.4 The recommendations must include supporting evidence that will provide a

reference as to why the recommendation is necessary and why it is considered

to be appropriate. Any follow-up actions required for Apotex products

manufactured by or on behalf of Apotex will be coordinated and supervised by

the appropriate Quality Unit. For Third Party manufacturers, the Apotex Quality

unit responsible for the oversight of the product or manufacturer will

communicate the information to the third party manufacturer and provide

oversight of the follow-up measures.

18.1.20.5 Any critical issue identified should be escalated as per GPOL-002 -

Management Controls - Governance, Management Notification, and

Management Review.


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18.1.20.6 Quality Assurance will monitor and update the status of the follow-up activities

related and/or required from the APR/PQR review report. A compliance record

will be generated for recommendations (as appropriate) with any required

CAPAs produced as child records of the associated recommendation

compliance record. The status updates of the activities will be communicated

to the appropriate management group periodically (but not less than quarterly)

until they are completed.

18.1.21 Approvals Page

18.1.21.1 This section documents Reviewer and Approver signatures.

Note: Completed APR/PQR reports should be made available to Third Party

Customers who require the document as outline in Quality Agreements with

that customer.

19.0 Data Analysis and Trending

19.1 Appropriate statistical analysis must be applied to the review of relevant quality data.

19.2 Non-statistical analysis such as reviews of graphs shall be interpreted for the reviewer as to its

explanations and conclusion.

19.3 The data generated from the batch or product shall be trended using the appropriate statistical techniques

such as time series plots, control charts, etc to draw the conclusions, if any. This will help the

manufacturer to take any corrective or preventive action, should manufacturer find the process to be out

of control.

19.4 The data should be trended and analyzed to determine if (i) if the process is in control, (ii) whether the

process continues to be in validated state and (iii) if any improvements are indicated based on process

trends.

19.5 Appropriate graphical and statistical tools and methodologies shall be applied to demonstrate valid

quantitative and qualitative interpretations. Such tools and methodologies may include, statistical control

charting, and process capability studies.

19.6 Statistical analysis must be conducted and interpreted by qualified individuals.

20.0 System Monitoring

20.1 Key Performance Indicators (KPIs) of the APR/PQR program, including on time completion, must be

established and monitored through monthly reporting with escalation as needed. Corrective actions must

be implemented if required by KPIs.


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21.0 Differences Between FDA and European Product Reviews

21.1 Refer to Table 2 for guidance when preparing two separate Annual Product Quality Reviews for different

Regulatory Agencies.

Table 2: Differences between FDA and European Product Reviews

Objective FDA EU / PIC/s / Canada

Determine appropriateness, or need to change, product

specifications

Required Required

Determine appropriateness, or need to change,

specification for starting materials

Not specified Required

Review the need to change manufacturing procedures Required Not specified

Review the need to change in-process controls Required Not specified

Verify consistency of existing process Not specified Required

Need for re-validation of processes Not specified Required

Highlight trends Expected Required

Identify product/process improvements Not specified Required

Identify corrective actions Expected Required

Consider previous reviews Expected Required

Grouping of products Not allowed Allowed

22.0 Risk Assessment and Revalidation Programs

22.1 Risk assessments must be conducted for all products where the final conclusion is Acceptable with

conditions or Unacceptable. The risk assessment must be conducted per appropriate tools described

in the Quality Risk Management Global Policy [GPOL-014] and Global SOP. The outputs of the risk

assessment shall include conclusions and recommendations for risk reduction, risk avoidance, or risk

mitigation. CAPA activities generated as a result of the risk assessment must be approved by Quality

Assurance. For all product reviews receiving an Unacceptable rating, Site and Corporate Quality and

Regulatory Management must be promptly notified as per the Management Control Global Policy [GPOL-

002].


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23.0 External References

Document Title Reference Type

Health Canada - C.02.011 Manufacturing Control, Section 51 Annual

Product Quality Review Section 51 55

(www.hc-sc.gc.ca)

Health Canada Regulation

Code of Federal Regulations, Title 21, Volume 4, Revised April 1, 2012

"Title 21, Food And Drugs, Chapter I-Food And Drug Administration,

Department Of Health And Human Services,

Subchapter C-Drugs: General

Part 211, Current Good Manufacturing Practice For Finished

Pharmaceuticals"

Subpart J, Records and Reports

Sec 211.180(e), General Requirements

Sec 211.192, Production Record Review

(www.fda.gov)

US FDA Regulation

EudraLex, The Rules Governing Medicinal Products in the European

Union, Volume 4, EU Guidelines for Good Manufacturing Practice for

Medicinal Products for Human and Veterinary Use

Part 1, Basic Requirements for Medicinal Product

Section 1 Quality Management Product Quality Review,

(www.ec.europa.eu)

European Commission

Guidance

(EMEA,MHRA)

Pharmaceutical Inspection Convention, Pharmaceutical Inspection Co-

Operation Scheme, Guide To Good Manufacturing Practice For

Medicinal Products, 15 January 2009

Chapter 1, Quality Management

Section 1.4, Product Quality Review

(www.picscheme.org)

PIC/S Guidance


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24.0 Revision History

Revision

No.

Effective

Date

Change

Control

No.

Description / Reason for ChangeAuthor of

Revision

1 Current 75529 1. Updated the 'Scope', General

Training Requirements and Roles and

Responsibilities sections of the

document to align with the current

GPOL/GSOP template.

2. Update Document references where

applicable for consistency with new

referenced document numbers and

titles.

3. Updated Regulatory Department

responsibilities; Update product

grouping strategy and exclude

salvaged product term for clarity.

4. Excluded redundant Specification

content comparison with the product

dossier requirement.

5. Updated additional sections

throughout the documents where

applicable as appropriate for

compliance and alignment with

established process.

Elaine Leong,

Manager, QA

Global Policy and

Standards

0 10/03/2013 52820 New Global Standard Operating

Procedure GSOP-011-005 Annual

Product Quality Reviews

Elaine Leong,

Manager, QA

Global Policy &

Standards


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Exhibit A: Annual Product Quality Review Process Overview


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Exhibit B: Annual Product Quality Review Relationship to the Quality System

APR

CAPA and

Improvement

Compliance to

license, and

applications

Validation,

Re-Validation

and VMP

Specifications

and Controls

Product Risk

Management


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APPROVALS AND SIGNATURES

UserName: Ross Maclean (apotexmaclean) Title: Senior VP, Scientific & Regulatory Aff Date: Thursday, 17 July 2014, 02:27 PM Eastern Time Meaning: Approval ================================================

UserName: Brian Magerkurth (apotex\bmagerku) Title: EVP, Global Supply Operations Date: Thursday, 17 July 2014, 02:34 PM Eastern Time Meaning: Approval ================================================

UserName: Pradeep Sanghvi (apotex\psanghvi) Title: Executive Vice President, Global R&D Date: Thursday, 17 July 2014, 07:47 PM Eastern Time Meaning: Approval ================================================

UserName: Victoria Chester (apotex\vchester) Title: Global Director, QA Policy and Systems Date: Friday, 18 July 2014, 12:38 AM Eastern Time Meaning: QA Approval ================================================


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g Sop 011005

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