Annual Product Quality Review APQR

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Annual Product Quality Review (APQR)

A complete guide on view of different regulatory bodies and comparison

Annual Product Quality Review (APQR) is a review report required by regulations from
different healthcare regulatory authorities. When following the process, the medicine
manufacturer required to periodically review that the finished products are consistently
meeting the implemented quality standards for the product under review. APQR is also
called as Annual Product Review (APR) or Product Quality Review (PQR).

According to the regulation, the drug product manufacturers should review the
manufacturing process and quality parameters minimum annually. The review will help to
determine the need for changes in drug product specifications or manufacturing or control
procedures. Furthermore, the objective of the APQR or regular periodic assessment is to
verify the reproducibility of the process, the suitability of current specifications of materials
and finished product, highlight any trends, and identify product and process improvements.

You can see these requirements in most of the regulatory guidance and regulations. I tried
to cover a few of the guidance in this article to provide an overview and the importance of
the requirement. You will find many differences in different guidelines. We will see those
differences in the requirements for the United States, European Union requirements,
guidance published by ICH (The International Council for Harmonisation) and PICS
(Pharmaceutical Inspection Convention Pharmaceutical Inspection Co-operation Scheme).

A. Guidelines applicable for APQR

Following are the requirements for Annual Product Quality Review specified in various
guidelines and regulations.
B. Comparison between different guidelines for APQR

More or less, the objective to carry out an annual product quality review is to verify the
product behavior over the period, consistency of the process, appropriateness
specifications of starting materials and finished product, and to understand the trends to
identify an opportunity for product and process improvements. The following table will
provide you the guideline to prepare the Annual Product Quality Review SOP (Standard
Operating Procedure). The procedure is typically part of Quality Assurance department
SOPs.

21 CFR
211 ICH
Requirements for Annual Product Quality Review PIC/S EU WHO
211.180 Q7
(e)
Appropriateness of specifications for finished
Y Y N Y Y
product
Appropriateness of specifications for starting
Y N N Y Y
materials including packaging materials
Determine the need for changes in manufacturing
N Y N N N
and control procedures
Out of trend and to required process or product
Y N N Y Y
improvements
Consistency of the existing process Y N Y Y Y
Evaluation of data and an assessment for
Y N Y Y Y
requirement of CAPA
Frequency, mandates and flexibilities
Product grouping e.g., Oral solid, liquid, or sterile Y N Y Y Y
Taking into account previous reviews Y N N Y Y
Even if no manufacturing has occurred in the
review period, the quality review should be
conducted per section ICH Q7, paragraph 2.50, and N N Y N N
include stability, returns, complaints, and recalls.
(Q and A published by FDA April 2018)
Review requirements for APQR
Review of all representative batches (including
N Y N N N
approved and rejected)
RM (starting) and PM (packing) review Y N N Y Y
Review of new sources Y N N Y Y
Review of supply chain traceability of active
Y N N N Y
substances
Critical IPCs and FG results Y Y Y Y Y
OOS batches and investigation Y Y Y Y Y
Deviations or NCs with investigation Y Y Y Y Y
Effectiveness of CAPA taken for an investigation. Y N N Y Y
Process and method changes Y N Y Y Y
MA variations submitted, granted or refused Y N N Y Y
A review of results of the stability monitoring
Y N Y Y Y
program
Stability studies and trend Y N N Y Y
Complaints, recalls and return and its investigation Y Y Y Y Y
Review of salvaged drug products N Y N N N
Appropriateness of previous product process or
Y N N Y Y
equipment CAPA
For new MA and variations to MAs/ dossiers, a
Y N N Y Y
review of post-marketing commitments
Equipment and utilities qualifications-Water-HVAC-
Y N N Y Y
Compressed Air
Contractual or technical agreements Y N N Y Y
Responsibilities and post review requirements
Follow-up actions and verification during internal
Y N N Y Y
audits
Timely completion of CAPA Y N Y Y Y
Responsibility of quality review. Y N N Y Y
Responsibility of QP/ Quality person for timely
Y N N Y Y
completion and ensure correctness

C. Documentation for the APQR

In this section, I am providing an outline and general idea for the preparation of APQR. A
reader can use this section to develop an APQR template.

Batch manufacturing details:

In this section of the APQR, provide details regarding the batches manufactured between
periods under review. The details shall contain information about batch Size and status of
the batches. The details can be organized under the heading, number of batches
manufactured, released, rejected, under manufacturing process, the total number of
batches, batches shipped into the market.

Review of starting materials including packaging materials:

Guidelines recommend giving more emphasis on the review of new vendors introduced
during the review period. The review also covers the quality parameters of key raw
materials. The details can be organized by collecting the data such as material code, name
of the material, unique batch number, name of the approved supplier or manufacturer. The
review also should cover a number of rejections in the year. The quality index for each
material can be calculated by factoring the number of rejects per year per vendor out of
total supplies during the review period.

Review of API supply chain traceability:

In this section of the document, the supply chain traceability of the API should be reviewed.
This will include quality agreement arrangements, product supply chain routes assessment,
transportation condition, and distributor involved if any. If the distributor is involved and
intermittent storage is happening, the distributor should also be part of supply chain
traceability.

Review of qualification status of equipment and utilities:

In this section, a review shall be carried out for the utility and equipment qualification
status. Data can be tabulated for equipment name, equipment number, last qualification
date, next due date. In the case of utility systems where continuous monitoring is in place,
trend data can be reviewed, such as environmental monitoring, water system trend
monitoring. The review can also be expanded for review of major changes, breakdowns, and
maintenance.

Review of product process validation and changes:

Provide information regarding Provide information regarding the introduction of a new

commercial product, change in the manufacturing process, change in equipment, and
change in the manufacturing area or location. Also, discuss corresponding process
validation carried out or quality comparison done. The details that should be included in this
section can be change control number, batch numbers that were validated as an outcome
of change, and the outcome of the validation exercise.

Data regarding critical process parameters and critical quality attributed should be
considered for review. Appropriate statistical evaluation should be considered for the
evaluation of compiled data.

Review of critical in process parameters:

In this section, the Critical Process Parameter (CPP) shall be compiled from the batch
manufacturing records. Examples of CPPs for tablet and capsule manufacturing would be,
granulation, dry mixing, wet mixing, drying, blending, compression, capsule filling, and
coating. Examples of injectable products are solution preparation parameters such as
mixing time, preparation time, filtration time, sterilization time, sterilization parameters,
filling machine speed, rejects, etc.

These data should be evaluated statistically to understand the robustness of the process.
Process capability index is the best tool, which can be used to understand process control.

As an outcome of the evaluation, control limits or trend limits can be calculated. The
batches which will be manufactured in a subsequent year should be monitored against the
calculated control or trend limits by the manufacturing supervisor to ensure that batch
under manufacturing is done under a controlled condition and potential for batch failure
because of process deviation could be eliminated.

Review of in-process controls or analytical records of intermediate stages:

Similar to the CPP, Critical Quality Attributes (CQAs) at each stage of monitoring should be
monitored and trended. This will help to understand the robustness of the manufacturing
process at each stage of manufacturing. Similar to the CCP discussed in the above section,
the trend limit should be calculated and future batches should be monitored against the
derived trend limit. The limit shall be reviewed every year for the need for any changes
based on historical data.

Review of analytical records of finished product:

The same approach can be applied to review the CQA at the finished product stage.

Received complaints about the product during the review period should be trended to
evaluate the status of the complaint, outcome of an investigation, implementation of CAPA,
and CAPA effectiveness. The review should emphasize on verification of any repeat
complaint because of CAPA failure.

In this section, data should be compiled regarding quality related returns, product recalls
and investigations performed. The status of CAPA implementation should be verified to
ensure that it is adequately implemented to prevent reoccurrence.

Review of Change Control:

Details of all changes concerning the process or analytical methods or any other product-
related change shall be compiled. Details of change and status of change control closure.
Should be documented.

Review of Deviations, Out Of Specification and Out of Trend:

Details should be compiled regarding significant deviations, Out Of Specification and Out of
Trend or NCs, its investigations, and the effectiveness of CAPA. Details of root cause and its
category and status of investigation should be reviewed.

Review of stability program and product retain sample:

Details stability study initiated during the review period as well as a review of the ongoing
stability study should be done under this section. The data set should include but not
limited to the batch number, packaging profile, reason for stability study, current status, and
outcome of study up to the review period.

Review of retains sample should cover outcome of visual checking.

Review of marketing authorization/ dossier:

This section should cover a review of MA variations, submitted/ granted/refused, including

those for third country (export only) dossiers. Post-marketing commitments review for new
MAs and variations to MAs should be included under this section.

Review of technical/ contract agreements:

In this section, technical/ contractual agreements for all the GMP regulated outsourced
activities should be review for validity and status. This will include but not limited to
contract manufacturing, testing, packaging, labeling validation, etc.

Review of technical agreement between manufacturer and marketing authorization

holder:

In this section, technical agreements between manufacturer and MA holder should be

reviewed for validity and status.

Verification of previous reviews or previous year APQR:

In this section of the document proposed actions during the previous APQR should be
verified for the implementation status. This also shall include a review of products which
was under manufacturing while approval of previous year APQR.

A review of all changes carried out to the processes or analytical methods:

This section shall cover a review of revisions made in the documents for manufacturing
processes or analytical methods. During this review, the status of all the documents shall be
reviewed for their validity.

Review of media fill (applicable for sterile facility):

During this review, coverage of product under a matrix of media fill shall be verified.

Review of environmental monitoring:

For sterile manufacturing facility adequacy of the environmental condition is very essential.
In this section of the document, environmental monitoring trend should be reviewed for
excursions, frequency of excursions and adequacy and effectiveness of implemented CAPA
should be reviewed.

Review action implementation status of regulatory deficiency for the product:

During the APQR, it is also important to verify the CAPA implementation status and
effectiveness review status of regulatory deficiency (if any observed).

Conclusion and recommendations:

Once the review gets completed, a conclusion on the review outcome should be derived.
The conclusion should include but not be limited to improvement opportunities for
production process and specifications, implementation status of previous year APQR
recommendation, CAPA effectiveness review, and process capability. In the conclusion
statement, it should be ensured that all the objective of preparation of APQR is been met or
not.

The APQR/ PQR should be reviewed by a cross-functional team of manufacturing, quality

control, regulatory affairs, and quality assurance. The review should be done with the intent
of identification of improvement opportunities to improve the process capability and
constancy.

D. Scheduling of APQR
Annual Product Quality Review is required to be performed for each product with annual
frequency. As indicated in the above table, the guidance suggests performing APQR on a
rolling or a rotation basis with annual frequency.

An example of rolling APQR can be done in such a manner that total products can be
divided into groups such as Group 1 – January to April, Group 2 – May to August, and Group
3 – September to December. As per this example, the APQR of Group 1 product needs to be
completed from January to April every year.

While preparing the schedule, the priority can be decided on a risk-based approach. This
priority can be decided with help of parameters such as the number of batches marketed,
customer complaints, product recall, stability failures, product deviations, out of trends,
customer requirement, etc.

E. Importance of statistical evaluation during product quality review

The statistic will help you understand process drifts over the period, exceptions or process
outliers, an opportunity for improvements in processes, determining limits for Out of Trend
(OOT) for ongoing batches, redefining the in-process controls and specifications, etc.

Statistical calculations such as minima, maxima, averages, relative standard deviation

(RSD), process capability index (Cp), minimum process capability index (Cpk), process
performance index (Pp), and minimum process performance index (Ppk) shall be applied
where appropriate. The statistic should be applied to collected CPPs and CQAs. The data
also should be presented in the form of control charts.

1.
Calculation formula for Cp, Cpk, Pp and Ppk:

USL: upper specification limit;

LSL: lower specification limit;
Mean: grand average of all the data
Sigma hat: estimated inherent variability (noise) of a stable process
SD: overall variability

Click on following button and get Free Excel sheet for calculation of Process Capability
Indices – Cp, Cpk, Pp, and Ppk.
Click to this link to know more about Process Capability Indices – Cp, Cpk, Pp, and Ppk

Difference between Cpk and Ppk:

Cpk represents the potential process capability (i.e. how well a given process could perform
when all special causes have been eliminated).

Ppk addresses how the process has performed without the demonstration of the process to
be stable.

If Cpk is approximately equal to Ppk, the process is in statistical control

If Cpk is significantly different than Ppk, the process is not in statistical control

The reality is that Cpk is a better estimate of the potential of your process. It represents the
best your process can do and that is when the within subgroup variation is essentially the
same as the between subgroup variation.

Reference: www.spcfor excel.com, www.fda.gov, presentation by Lawrence X. Yu, Ph.D.

titled, Use Process Capability to Ensure Product Quality.

Interpretation of Cpk index

Process capability index will help to understand the behavior of the process and gives an
idea about capability rating.

Depending on the types of data, there are two types of control charts.

Variable control chart: continuous numeric measurements (e.g. assay, dissolution,

uniformity, impurity level)

Attribute control chart: discrete data (pass or fail, or counts of defects)

Control charts can be used to determine whether the process is in a state of control or out
of control (unpredictable versus consistent).

There are eight rules to interpret the control charts. These rules are also called Nelson
rules. These rules were published in the October 1984 issue of the Journal of Quality
Technology in an article by Lloyd S Nelson. Interpretation of out of control for non-random
situations can be done as follows.
R-U-L-E – 1:
Any one point is > 3 SD from the average (Beyond Zone A). This means the point is Out of
Trend (OOT)

R-U-L-E – 2:
9 (or >) points consecutively are on the same side of the average. Some continued bias
happens. (In or beyond Zone C). This means the average is probably changed.

R-U-L-E – 3:
6 (or >) points consecutively are progressively increasing or decreasing. A trend exists. This
test indicates a drift in the process average. Such drift could be resulted because of wear
and tear, maintenance issues, improvement in skill, etc.

R-U-L-E – 4:
14 (or >) points consecutively alternating up and down, increasing then decreasing. This
pattern specifies that 2 systematically alternating causes are producing different results.
This could happen while using two alternate suppliers, monitoring quality for two different
or alternating shifts. The fluctuation is beyond the noise.

R-U-L-E – 5:
2 (or 3) out of 3 points consecutively are > 2 SD from the average in the same direction (In
Zone A or beyond). This is the signs early warning of process shift.

R-U-L-E – 6:
4 (or 5) out of 5 points consecutively are > 1 SD from the average in the same direction
(Zone B or beyond). Similar to the above point, this is an early warning indicator for potential
process shift. There is a strong propensity for samples to be slightly out of control.

R-U-L-E – 7:
15 points consecutively are all within 1 SD of the average on either side of the mean (within
Zone C). This indicates a smaller variation than expected.

R-U-L-E – 8:
8 points consecutively exist, but none within 1 SD of the avearge, and the points are in both
directions from the avearge (Within Zone B or A or beyond). This specifies that different
samples are affected by different factors. This could happen if different samples in a chart
were produced by 1 of 2 different machines, where one produces above average and the
other below.
By applying the above rules, one can identify an “out of trend” situation. There may be a
possibility for false alerts. However, adopting the approach to identify OOT, investigate and
rule out rather than completely ignoring the things. Investigating OOT will help to prevent
potential failures.

Reference from: https://www.leansixsigmadefinition.com/

F. Retention period of APQR

By general rule, any document related to batch should be stored for product expiry + 1 year
or five years, whichever is longer. However, sometimes APQR and continuous process
verification are merged and documented as one record. Continued Process Verification is a
requirement as per current FDA guidance on Process Validation: General Principles and
Practices, January 2011. In this guideline, the requirement of 21 CFR 211.180(e) is linked
with the Continued Process Verification (Stage 3 – of process validation). Process
validation documents are generally stored for the lifecycle of the product. It is always
prudent to store the APQR record for product lifecycle because, individual batch record
retention time is product expiry + 1 year or five years, whichever is longer. APQR will serve
as a database for the product and can act as a tool for investigation, process improvement,
and product history.

G. Conclusion

APQR conclusion should consist of these three elements (i) Assessment and conclusion,
(ii) Comments and recommendations, and (iii) Corrective Action and Preventive Action
(CAPA).

APQR is an indicator of a product’s health at a given point in time. Assessment and

conclusion can be derived based on the evaluation process in control. A review of data and
statistical evaluation would indicate that process is in a state of control and producing
consistent quality of product and confirms that the process continues to function as
validation or it is opposite. If the review indicates that the process is not in the state of
control, improvement opportunity needs to be evaluated.

Comments and recommendations can be made based on the above assessment. The
recommendation can be applicable in both cases, i.e. process found robust or the process
is not producing a consistent quality of the product. If the process is robust, specification
limits can be tightened further to ensure that future products will be produced with
tightened process parameters and any outlier identified can be investigated. On the other
hand, if the process needs improvement, an appropriate recommendation can be made to
improve the product performance.

Corrective Action and Preventive Action (CAPA) should be documented and tracked in case
of any recommendation is made. Reasons for CAPA should be documented. Corrective and
Preventive action should be completed in a timely and effective manner.

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