PURPOSE: 1.

To evaluate the performance of manufactured product versus the approved specifications

and expected quality attributes.
2. To identify trends in product quality or changes in Active Raw Material(s), In-Process, or
Finished Goods performance.
3. To propose the need for changes in product specifications or manufacturing processes or
control procedures.
4. Comply with 21 CFR Part 211.180 (e).

SCOPE: This procedure is intended to describe the minimum requirements of 21 CFR Part 211.180 (e)
regarding evaluation of the batches and the batch records on an annual basis in order to
assure the quality standard requirements of the product. This procedure covers the approved
marketed products manufactured for commercial distribution.

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QA 1.0 During the beginning of each calendar year, QA will obtain a list of approved
products from Regulatory Affairs (RA). Refer to Attachment I - APR Flow Chart for
reference.

2.0 Based on this list, QA will generate a schedule of the Annual Product Reviews
(APR) due for the year.

2.1 The schedule will include, as a minimum: product, strengths, product codes,
the review period and approval due date.

2.2 The review period is determined by each product’s approval date. For
example, a product whose approval date is June 15, 2002 will contain data
from batches manufactured/dispositioned within the June 15, 2002 to June
14, 2003 reporting period. The review period encompasses 1 year of data
from manufactured/dispositioned lots. APRs for different strengths of the
same product with similar approval dates may be combined.

2.3 APR packages will not be compiled for products for which there were no lots
manufactured or products that have been discontinued during the review
period. Although those products were not manufactured, product quality will
be monitored and documented throughout their shelf life through the
following systems: stability study programs, customer complaints, and
retention samples review.

3.0 QA will coordinate preparation of the APR report, which consists of two parts: the
Executive Summary and the Data File.

4.0 The Executive Summary consists of the following sections. See section 7.0 for
detailed information that will be included in the Executive Summary.

4.1 Cover Page

4.2 Approval Page

4.3 Abstract

4.4 Active Raw Materials

4.5 Product Review

4.6 Change Control

4.7 Deviations/Planned Variances

4.8 Laboratory Investigation Reports (OOS/OOT)

4.9 Stability

4.10 Complaints

4.11 Field Alerts/Recalls/Returned Goods

4.12 Retention Samples

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QA 4.13 Corrective Actions

4.14 Attachments

5.0 The Data File consists of the supporting documentation, such as raw data, charts,
graphs, Specification sheets, Certificates of Analyses, etc. The Data File will be
retained in QA until the Executive Summary is approved.

6.0 Compilation Requirements

6.1 Charts/Graphs generated for the Executive Summary must have the
following in the header: product name, strength, product code, and review
period. In addition, charts/graphs must have “Prepared By/Date:” and
“Verified By/Date:” as a footer and be initialed and dated by the preparer
and the verifier. Charts/graphs will be generated if there are five or more
lots/entries available, otherwise no charts/graphs are required. This does
not apply to the Data File.

6.2 100% of the manufactured lots within the review period will be reviewed.

6.3 For Deviations/Planned Variances, LIRs and Stability investigations

addressing product with multiple actives, specify which active is involved.

6.4 List the Stability lots and the purpose of study.

6.5 Ensure a statistical analysis is conducted to determine trends.

7.0 Compile the Executive Summary. The summary will include the following sections
with the indicated requirements.

7.1 Cover Page

7.1.1 Product name and strength

7.1.2 Application number

7.1.3 Application approval date

7.1.4 Review Period

7.2 Approval Page

7.2.1 Product name, strength, and product code

7.2.2 Review Period

7.2.3 Compiled By and Date

7.2.4 Assessment of Manufacturing Process Changes

7.2.5 Product Review

7.2.6 Approval Signatures and Dates

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QA 7.2.7 Total Number of Pages

7.3 Abstract

7.3.1 A brief overview of product performance during the review period.

7.3.2 Report any trends or changes to (Title of escalation responsible

party) and identify any corrective actions.

7.4 Active Raw Material(s)

7.4.1 Evaluation of the active raw material(s) used in the manufacturing

of the drug product. Characteristics to be evaluated include, as
applicable, but are not limited to: Assay, Specific Rotation, LOD,
pH, Particle size, Bulk Density, and Impurities. Explain any out of
specification results and outliers.

7.4.2 Name of manufacturer.

7.4.3 Number of active raw materials lots utilized.

7.4.4 Number of active raw materials lots rejected.

7.4.5 Compare full tested active raw material lot(s) results to their
respective Certificate of Analysis.

7.4.6 Evaluate data for trends, shifts, and outliers.

7.5 Product Review

7.5.1 Evaluation of in-process attributes. This includes, as applicable:

packaging yield, blending, theoretical and total accounted yields,
weight, thickness, hardness, disintegration time, friability,
compression theoretical and total accounted yields, and film
coating theoretical and total accounted yields.

7.5.2 Evaluation of finished product data: Assay, Content Uniformity,

and Dissolution. Report Chromatographic Purities.

7.5.3 Number of lots manufactured. For multiple strength APRs, state if

any product codes had no manufactured lots.

7.5.4 Number of lots released.

7.5.5 Number of lots not dispositioned.

7.5.6 Number of lots rejected, lot number, cause, and any

corrective/preventive action taken.

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QA 7.5.7 Identify any experimental lots converted from rejected finished

good lots.

7.5.8 Identify the lots not yet dispositioned. These lots will be carried
over to the next review cycle, if applicable.

7.5. 9 Generate Control Charts for in-process attributes and finished

product data, if applicable, as an attachment. Address any control
parameters that are visually verified but cannot be graphed
(Examples: hardness may be a range; impurities may be a < value
or a NMT value).

7.5.10 Evaluate Control Charts for trends, shifts, and outliers.

7.5.11 Identify, review, and summarize the results of any process and
method validation/re-validation, if applicable.

7.6 Change Control

7.6.1 Review Change Controls issued during the review period.

7.6.2 Report the change controls, including but not limited to,
Specifications (Active Raw Materials and Finished Goods), Batch
Records, Test Methods, Packaging Components, Bills of Material
and Labeling.

7.6.3 Verify that any changes in the manufacturing process, formulation,

batch size and/or equipment for the lots manufactured during the
review period have been approved, validated, and qualified.

7.6.4 Generate a Pareto chart.

7.6.5 Details of the manufacturing process change(s) affecting validated

processes will be in the Data File.

7.7 Deviations and/or Planned Variances

7.7.1 Review and report the deviations and/or planned variances

generated within the review period and determine if there are any
developing trends.

7.7.2 Compare the product related deviations and/or planned variances

initiated during the review period to previous year’s APR.

7.7.3 Generate a Pareto chart.

7.8 OOS/OOT

7.8.1 Review and report the OOS/OOT generated within the review
period and determine if there are any developing trends.

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 7.8.2 Compare the product related OOS/OOT initiated during the review
period to previous year’s APR.

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QA 7.8.3 Generate a Pareto chart.

7.9 Stability

7.9.1 Evaluate the annual stability data for product lots in the stability
program. The Stability Results Summary shall include any
Stability Study Termination/Modification Request documents.

7.9.2 Data (assay, dissolution, hardness and impurities, as applicable)

from the stability studies will be entered into regression data
tables. Stability regression analyses will only be generated when
there are four or more time points.

7.9.3 Generate graphs for regression profiles using Statistical software.

If the data is non-continuous, a data table will be provided in place
of regression graphs. Include confidence interval on charts if the p-
value is <0.05.

7.10 Complaints

7.10.1 Review and evaluate the reported complaints.

7.10.2 Generate a Pareto Chart.

7.11 Field Alerts/Recalls/Returned Goods

7.11.1 QA will summarize any field alerts initiated during the review
period.

7.11.2 QA will obtain documentation from Complaints Administration

regarding any recalls initiated during the review period.

7.11.3 Based on the QA Product Release database, determine if any

products were returned to inventory and/or rejected for
destruction.

7.11.4 Report the Recalls and Returned Goods for the review period.

7.12 Retention Samples

7.12.1 Complete an Annual Retention Sample Visual Inspection Report.

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QA 7.12.2 This reports the overall appearance (color changes and broken
tablets) of the retained samples of the product. In addition, it
provides a list of lots that are not due for visual inspection until
one year past their manufacturing date and a list of lots that have
completed their annual visual inspection.

7.12.3 Review and report the results of the annual visual retained
samples.
7.13 Corrective Actions

7.13.1 Based on APR Conclusions, corrective action(s) will be

determined and listed.

7.13.2 A corrective action must also include the responsible department

and target due date.

7.13.3 The implementation of corrective actions will be verified during

the next review period and will be documented in the APR.

7.14 Attachments

7.14.1 The appropriate Controls Charts, Linear Regressions, Pareto

Analyses and Data Tables will be attached and referenced.

8.0 Once the Executive Summary has been compiled, it will be signed and dated by
QA and then routed to the Annual Product Review Committee for approval. (list
titles of the approving committee)

QA 8.1 After reviewing the APR, determine whether the manufacturing processes
remain in a validated state. If there is a question about the state of the
manufacturing processes, call a meeting with the APR Committee to
review the APR.

8.2 If it is determined that the manufacturing processes remain in a validated

state, Indicate this in the conclusions section of the APR.

8.3 If it is determined that the manufacturing processes do not remain in a

validated state, Indicate this in the conclusions section of the APR.

8.4 Additional information may be provided in the Comments section.

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Quality Operations 8.5 Assure that any corrective actions identified are implemented. Inform
Corporate Officers of any product-related issues.

QA 8.6 Comments during the review process may lead to revisions of the
Executive Summary including associated attachments. Any applicable
revisions made shall have “Prepared By and Verified By” dates occurring
between the compilation date and the final approval date. Revisions will
be re-routed to previous approvers of the Executive Summary. Original
and revised copies of the Executive Summary will be retained in the Data
File.

8.7 The Executive Summary must be approved within 90 business days from
the last day of the review period.

8.8 In the event that the APR goes beyond the specified time period for the
review process, a planned variance will be initiated, documenting the
reason for the delay and the timeline for completion.

8.9 In the event an amendment is necessary, the amendment document shall

be incorporated following the original document. The header shall include
the product name, strength, code and review period. In addition, the footer
shall consist of “Amended By/Date” and “Verified By/Date”. A designated
letter (A, B, C, etc.) will be integrated to the respective page number
affected. Amendment(s) must be re-routed to the APR Committee for
approval.

8.10 Report pagination will occur after the document has been approved.

9.0 Notify the CAPA Administrator regarding corrective action(s), if applicable. This will
be monitored through Corrective Action Preventive Action System (CAPA).

10.0 File the approved APR Executive Summary and Data File with Documentation
central archive.

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