ANNUAL PRODUCT QUALITY REVIEW (APQR)/ PRODUCT QUALITY REVIEW (PQR)
This Annual product Quality review should be conducted with the objective of verifying the repeatability of existing processes, the appropriateness of current specifications for raw materials and finished products, identifying any trends and identifying any improvements to products and processes. It helps establish preventive measures, and to detect any regulatory changes or to introduce quality. This review is conducted annually, and documented, taking into account the results of the previous review.
Corrective Action: Action taken to eliminate the causes of an existing non-conformity, defect, or other undesirable situation, in order to prevent a recurrence.
Preventive Action: Action taken to eliminate the cause of a potential nonconformity, defect, or other undesirable situation, in order to prevent occurrence.
CQA: Critical Quality Attribute refers to a physical, chemical, biological, or microbiological
Property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.
CPP: Critical Process Parameter refers to a process parameter whose variability has an impact on a critical quality attribute and, therefore, should be monitored or controlled to ensure the process produces the desired quality.
UCL: Upper Control limits/LCL: Lower Control limits: They indicate the threshold at which the process output is considered statistically ‘unlikely’.
APQR is a periodic review of batch documents of product analytical data, stability data, product complaints etc., to determine the trend and issues. APQR shall include the review of processing parameters and quality parameters.
APQR Shall be prepared for all products manufactured in one year beginning from 1st January to ending 31st December. Graphical representation of APQR is done by Minitab Software.
APQR shall be prepared for a product that has five (5) or more batches manufactured in a year.
If less than five batches are manufactured during the review period of APQR, the same batches are included in the APQR of next year.
APQR of all products shall be prepared in three months of time frame.
The different strengths of a drug product, which contain the same source materials, same manufacturing process, and identical equipment can be clubbed together in a single APQR/PQR provided having the same qualitative and quantitative composition (dose-weight proportion formula) and same specification parameters.
An APQR/PQR for each product shall include a review of the following data:
1.0 Product Quality Complaints:
- Number
- Type/Classification (including Adverse Reaction Complaints)
- Severity
- Trends
- Investigations /CAPAs, if any
- Status (Open/Closed)
2.0 Product Recalls, Market Withdrawals, and Regulatory Alerts.
- Number
- Customer
- Severity/depth (Class)
- Associated CAPAs, if any
- Status (Open/Closed)
3.0 Product Returns-Includes returned or salvaged APls / Drug Products:
- Number
- Customer information, if available
- Customer locations, if available
- Reasons for return
- Associated shipping records, if available
- Product Storage Conditions
- Investigation results and decisions, as applicable
4.0 Process Controls:
- Identity of CPPs
- Excursions from CPPs
- Deviations and corrective actions associated with CPPs
- Review CPPs for trends to assure process reliability.
5.0 Critical Quality Attributes (CQA):
- Calculation of a process capability for each CQA.
- In-Process Critical Attributes: All critical in-process attributes shall be reviewed for emerging trends and compliance with in-process specifications. The specific requirements for each product may vary depending on individual product needs. The following dosage-wise in-process attributes, as applicable (but not limited to), may be considered and reviewed
| Dosage Form/AP! | Critical In-Process Quality Attributes |
| Blend for Tablets/ Dry Powder/ Powder for Oral Suspension | Loss on Drying (LOD)/Water Content, Assay, Blend Uniformity Analysis (as applicable) |
| Tablets | Average Weight, Assay, Disintegration Time, Hardness, Thickness, Friability, Uniformity of Weight |
| Liquid | Average Fill Volume, pH, Assay |
| Oral Liquid | Average Deliverable Volume, pH, Specific
Gravity, Assay |
| Ointment | Average Weight, pH, Assay, Viscosity, Related Substances (RS) |
| Intermediate and Final Stage) | Assay, Water Content/ LOO, pH, Reaction Parameters |
6.0 Evaluation of Batch Yield:
Final Batch Yield/ First Crop Yield Data (as applicable) of each batch shall be incorporated in APQR/PQR. The actual batch yield shall be reviewed against the standard yield mentioned in the production record. Batches with a yield outside the acceptable range shall be listed together with a summary of the results of the investigations. Check the effectiveness of CAPA taken to correct the yield issues.
7.0 Rework/Reprocessing:
- Identity of associated lots.
- Causes for rework/reprocessing.
- Reference of associated site rework /reprocessing procedures.
- Reference to associated deviations and corrective actions.
- Reference to related filing due to rework/reprocessing.
- Results of associated laboratory testing.
- Requirements/results of any related stability testing.
8.0 Deviations
A list of critical and major deviations and any trends in minor deviations must be discussed along with associated corrective actions and preventive actions taken.
9.0 Review of Product/ Process related Validation activities and Qualification of Equipment and Utilities:
Review the current process with the initially validated process and provide a summary of Results and details about any revalidation requirements and any associated change control documentation.
- Change Control Records
Provide a summary of any product, process, component, or key raw material-related change control that may affect the quality of the product.
The summary shall include the number of product-related change control forms generated during the APQR/PQR period, their status (open/closed) & implementation date, if applicable.
11.0 Review of Laboratory Release Testing Data:
Finished Product Analytical Data: The trend analysis of finished product critical quality attributes (as applicable) shall be compiled batch-wise based on applicable product release specifications (in-house or compendia). Review/comparison of quality attributes of the finished product shall be done with validation batches. The following dosage-wise in-process attributes, as applicable (but not limited ‘to), may be considered and compiled:
| Dosage Form/API | Critical Quality Attributes |
| Tablets | Average Weight, Disintegration Time, Water Content/ Loss on Drying (LOD), Uniformity of Dosage Units, Dissolution, Assay, Related Substances, and Microbial Parameters. |
| Liquid (SVP) | Average Fill Volume, pH, Uniformity of Fill, Particulate Matter, Assay, BET, Sterility, and Related Substance. |
| Dry Powder Oral Suspension | Average Fill Weight, pH, LOD / Water Content, Assay, Related Substances, Stability of Constituted Suspension, Microbial Parameters |
| Oral Liquid | Average Deliverable Volume, pH, Specific Gravity, Assay, Related Substances, Preservative Contents, Residual Solvents, Microbial Parameters |
| APls | Water Content/ LOO, Assay, Related Substances, Residual Solvent. |
12.0 Review of Stability Testing Records:
The list of batches placed for stability studies during the review period and the
Reasons for their selection shall be included in APQR/PQR report.
The stability data of all batches placed under ongoing stability programs shall be reviewed and conclusions made to confirm whether data continues to support the defined product shelf life. In addition, the data should be reviewed to determine if the shelf life can be extended and any recommendations provided in the conclusion portion of the APQR/PQR.
A summary of any stability failures shall be included, with details of any ongoing remedial action / CAPA or further recommendations and highlighting any adverse trends or shifts apparent since the last review.
- Out-of-Specification (OOS) Results:
A listing of all batches with OOS Results along with the root cause(s) thereof (assignable or non-assignable), along with associated investigation findings, batch disposition, CAPA and OOS status (open/closed) must be included in APQR/PQR Report. Results of media fill positives and the associated investigations and CAPA was taken, wherever applicable, and must also be included in the APQR/PQR Report.
14.0 APQR/PQR Report.
A listing of all batches with OOT Results along with the reasons thereof (assignable or non-assignable causes), along with associated investigation findings, batch disposition, CAPA and OOT status (open/closed) must be included in APQR/PQR Report.
- Retention Samples:
Product-specific, periodic observation of control samples shall be reviewed which reveals critical parameters i.e. the appearance of the product, quality of packing, etc. found in compliance with specification and non-conformance if any.
16.0 Corrective Actions/Preventive Actions (CAPAs):
Provide a summary of product-associated CAPAs, including compliance to closure dates, extensions, reasons for extensions, and effectiveness of CAPAs to resolve issues (i.e. were their multiple CAPAs for the similar or same type of events and if so, what type of follow-up plan existed to correct the issue, refer to the Handling of Corrective and Preventive Actions (CAPA).
- Follow up from Previous APQR/PQR:
Review to verify investigation items \ Quality Management System (OMS) Records like Change Controls, Deviations, Product Quality Complaints, OOS, OOT, CAPA, Product Recalls, etc. opened during the preceding year’s APQR/PQR have been closed. A summary of the above review shall be included in the APQR/PQR.
18.0 Batch Manufacturing and Packaging Records:
- Provide adherence to CPPs, and COAs.
- Provide associated batch record documentation errors and resulting remediation steps as required, and time cycles to complete batch records reviews.
17.0 Review of Regulatory Updates:
Any changes/variations made against regulatory filing or marketing authorization and Their status shall be summarized in the APQR/PQR report.
18.0 Review of Technical Agreements/Quality Agreements:
A review shall be done to check the availability of Technical Agreements between Relax Pharma and all key customers/ vendors.
All reference technical agreements/quality agreements associated with contract manufacturers and packagers shall be reviewed to ensure that they are up to date or updated if required.
A summary of the above review shall be included in the APQR/PQR report.
Review timing for associated technical/quality agreements to show compliance with to review cycle.
Detail any non-conforming technical/quality agreement review cycles and CAPAs to resolve related review cycle issues. (Vendor Management for Raw Materials, Primary, and Printed Packaging Materials).
19.0 Facility Support Systems:
- Provide 12-month history of the facility (water, HVAC, compressed gas, environmental Control) related deviations/incidents and CAPAs.
- Provide a summary of actions to resolve significant facility issues and include resulting management and control of the affected product (if any).
20.0 Starting Materials (Key raw materials, APQR/PQR focus only):
Assessment of starting materials (including packaging product contact materials) and associated with handling procedures as they are introduced into the process (including special gowning requirements and associated testing requirements)
21.0 STATISTICAL EVALUATION AND TRENDING OF DATA
Data of ‘approved’ batches of the product under APQR/PQR shall be trended/ presented in tabular/ graphical forms (i.e. control charts, or graphs).
Control charts shall be prepared for all the critical quality attributes (in-process and finished forms)
Control charts may be plotted using USL, LSL, and Mean, as control limits (as applicable, but not limited to) and observed values of each batch under the APQR/PQR.
Each set of data shall be tabulated and/or graphed in such a manner as to easily exhibit results, deviations, and trends. Each graph/trend data must be reviewed to draw conclusions and concluding remarks must be added to the APQR/PQR.
While evaluating the trends of compiled data, appropriate statistical methods (e.g. using
UCL, LCL, and Process Capability Index (Cpk)) may be used to draw conclusions.
Cpk is a frequently used process capability index that measures how close a process is running to its specification limits [Upper Specification Limit (USL) and Lower Specification Limit (LSL)], relative to the natural variability of the process. It evaluates how well the data fits into the specification limits. A comparison is made by forming the ratio of the spread between the sample mean and process/product specifications, as measured by 3 standard deviation units (the process “width”).
A Cpk 1.33 is desirable, a value of Cpk = 0 implies that 50% of the process output falls beyond the specification limits. The larger the index, the less likely it is that any item will be outside the specification.
SUMMARY AND CONCLUSION OF APQR/PQR:
On the basis of compiled data, trend analysis, and statistical evaluation, an overall summary of the key findings shall be prepared and conclusions shall be drawn. These shall comprise the following information at the minimum, but not limited to:
- Provide an overall summary of the key findings and conclusions in ‘the APQR/PQR, listing quality issues, the status of action plans, responsible persons, and target dates for completion of action plans.
- A statistical assessment of the Critical Quality Attributes, Critical Process Parameters, product yields, and analytical test results to determine if there is any process variability that requires a CAPA.
- The APQR/PQR will summarize the review with an overall conclusion for the review with one of three following results:
- The process is in control and the review confirms that the process continues to function as originally validated.
- Actions are recommended – indicates that the process can continue to function, with a recommended corrective action plan in place to address issues identified.
- Corrective Action Required – indicates that the corrective actions must be completed and an assessment compiled to determine the impact of issues related to process validation (should the process be revalidated due to required corrective actions).
