August 2018

GUIDANCE NOTES ON
PRODUCT QUALITY
REVIEW
GUIDANCE NOTES ON PRODUCT QUALITY REVIEW AUGUST 2018

1.0 INTRODUCTION:

The purpose of this guidance is to communicate the expectation with regard

to the conduct of Product Quality Review. Product Quality Review is a GMP
requirement listed under Chapter 1 of the PIC/S GMP Guide for Medicinal
Products, effective since 1 Jan 2006.

2.0 WHAT IS A PRODUCT QUALITY REVIEW?

Product Quality Review is regular periodic or rolling quality reviews of all

licensed medicinal products, including export only products, which 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 to highlight any trends and to identify product
and process improvements.

The Product Quality review (PQR) is an effective quality improvement tool to

enhance the consistency of the process and the overall quality of the product.
The PQR will capture a broader view of product data, capturing trends and will
help determine the need for revalidation and changes, if any.

3.0 BACKGROUND

European Union (Eudralex):

The additional text “Product Quality Review” for Chapter 1 to the EU GMP
Guide has been adopted by the Ad hoc GMP inspectors Working group at
their first meeting in July 2003. The proposal of Product Quality Review arises
from the experience of Member States’ inspectorates where quality problems
with products on the market leading to recall could have been anticipated if
the manufacturer/marketing authorization holder had operated a system for
formally reviewing process consistency and trends.

US Food and Drug Administration (FDA):

The code of federal regulations (CFR) of Food and Drug Administration in

their 21 CFR – Parts 210 & 211 dictated the requirements of reviewing the
products annually. It is clearly stated under Subpart J - Records and Reports
211.180(e) that written records required by the part shall be maintained so
that data can be used for evaluating, at least annually, the quality standards of
each drug product to determine the need for changes in drug product
specifications or manufacturing or control procedures.

International Conference on Harmonization (ICH)

ICH Q7A GMP Guide for Active Pharmaceutical Ingredients requires

manufacturers to conduct annual quality review of the active pharmaceutical
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ingredients in order to know the consistency on the quality of products

manufactured through out the year.

4.0 PROCEDURE:

4.1 Product Quality Review should typically be carried out for each product
manufactured in the previous year. In the case of campaign manufacturing,
the review period can be extended beyond a year. Such extensions shall be
for a limited number of months and as described in a procedure. Along with
PQR, implementation of preceding years’ recommendations shall be
reviewed.

The Product Quality Review Report should contain at least the following
details:

(i) A review of starting materials and product contact primary

packaging materials used for the product, especially those from
new sources.

(a) Summary of all batches of starting and packaging materials

received in a year and their approval status;
(b) Summary of the suppliers/manufacturers of the materials;
(c) Compilation and analysis of the results of analytical tests for key
quality attributes such as description, identification, loss on
drying/water content by Karl Fisher, particle size, related
substances and assay;
(d) Compilation of the Certificate of analysis (COA) results obtained
from supplier/manufacturer, if the batch is released based on
supplier’s COA.
(e) Summary of details related to any significant deviations observed
such as rejection of vendor lots.

(ii) A review of critical in-process controls and finished product

results.

(a) Compilation(s) and analysis of in-process test results obtained from

the total number of batches manufactured in that particular year
e.g. weight variation, dimension, friability, hardness, disintegration
time, fill volume variation (such as for ampoules, vials, bottles), pH,
etc
(b) Compilation(s) and analysis of finished product test results such as
description/appearance, identification, pH, loss on drying/Water by
KF, viscosity, dissolution test, impurities and related substances,
degradation product (if any) and assay.

(iii) A review of all batches that failed to meet established

specification(s) and their investigation.

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(a) Summary of the number of failed batches/products. The list will

identify the batches that failed specifications and the root cause for
this failure, if identified
(b) Summary of the reasons for failure (assignable or non-assignable
causes)
(c) Summary of the completed investigation report(s) and corrective
actions taken.

(iv) A review of all significant deviations or non-conformances, their

related investigations, and the effectiveness of resultant
corrective and preventive actions taken.

(a) Summary of all deviations or non-conformance, together with

causes of the non-conformance, sorted based on data trending
(b) Compilation (using trend analysis) of corrective and preventive
actions (CAPA) taken

(v) A review of all changes carried out to the processes or analytical

methods.

(a) Summary of the changes, if any, made to the process e.g. change
of mixing time, blending time, drying time, changes in coating
process, changes in compression speed/time, changes in filling
speed etc
(b) Summary of the changes made to the analytical methods, e.g.
change of solvents, buffers, reagents, pH, change in composition of
mobile phase, change in HPLC/GC method parameters i.e. flow
rate, temperature, wavelength, run time, and change of HPLC/GC
column etc
(c) Review/report of the impact of the changes on the quality of the
product.

(vi) A review of Marketing Authorization variations

submitted/granted/refused, including those for third country
(export only) dossiers.

(a) Summary of the number of products registered with local and

overseas authorities that were covered in the review document, if
grouping by product type are done.
(b) Summary of the changes made to the product specification and
their status of approval. Document the regulatory decision.
(c) Summary of the number of products submitted but not
approved/refused by the local and overseas authority

(vii) A review of the results of the stability monitoring programme and

any adverse trends.

(a) Summary of the number of batches included for stability studies

during the review period and the reasons for their selection.

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(b) Summary of stability study report and results, i.e. out of

specifications for each conditions (real time/long term and
accelerated studies), together with a review of the results obtained
for stability indicating analytical tests.

(viii) A review of quality-related product returns, complaints and recalls

and the investigations performed at the time.

(a) Summary of batches returned due to potential quality defects,

together with the reasons.
(b) Summary of market complaints received in a year, together with
the nature of complaints.
(c) Summary of batches recalled, together with the reasons.
(d) Compilation of investigation reports prepared following market
complaints and the actions taken to prevent recurrence.

(ix) A review of adequacy of any other previous product process or

equipment corrective actions.

Summary of all corrective actions from previous product quality review

reports (other than those already listed in points (iii) and (iv), indicating
the implementation status of each of the corrective actions, and their
effectiveness in addressing the problems.

(x) For new marketing authorizations and variations to marketing

authorizations, a review of post-marketing commitments.

(a) Summary of any changes, in terms of the specification, registered

with drug regulatory authority, including overseas drug regulatory
authorities.
(b) State any post-marketing commitments and review the status of
these commitments.

(xi) The qualification status of relevant critical equipment and utilities,

e.g. HVAC, water, compressed gases, etc.

(a) Summary of the number of equipment / instruments in production

and laboratory department.
(b) Summary of the qualification/re-qualification status (policy) of
equipment / utilities used in the production processes and QC
laboratory indicating whether it has been qualified and it's next
qualification due date/policy. The actual results of qualification,
maintenance and calibration etc. would not be required in the PQR.

The Product Quality Report should cross reference to the respective

validation reports. Information available in the validation report need not be
repeated in the PQR.

(xii) A review of Technical Agreements to ensure that they are up to

date.
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(a) Review of written contract covering the technical requirements on

periodic maintenance of production and laboratory equipment
between the manufacturer and supplier. A summary report would
be sufficient.
(b) Review of written contract covering the technical requirements
between contract giver and contract acceptor (if any). A summary
report would be sufficient.
(c) These technical agreements need to be annually reviewed to
determine whether is there need to further revise/update the
technical agreements.

The attached Annex 1 shown at the end of this document is meant to provide
an overall summary at a glance on the corrective and preventive action
undertaken while compiling the data for Product quality review.

5.0 HOW TO IDENTIFY TRENDS, INTERPRET DATA, AND DRAW

CONCLUSIONS FROM THE DATA

5.1 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.

5.2 The data should be trended and analyzed to determine if (i) the
process is in control; and (ii) the process is capable. Control limits should be
established through trending. The appropriateness of current specifications for
both starting materials and finished product should also be determined. In
addition, it is important to highlight any trends observed and to identify product
and process improvements. Improvement plans and actions should be
initiated and taken if the process is found to be out of control or has low
capability indices.

5.3 The data may be analyzed using the following techniques:

(a) Control Charts

Processes should be demonstrated to be in control, and one of the
ways to demonstrate this is the use of charting techniques commonly
known as the Shewhart Control Charts. The use of such charts
(example: X-bar charts, R-charts and Moving Range charts etc.)
enables the manufacturer to determine upper and lower control limits,
and identify trends (examples: upward trend of data, shift in mean
etc.) so that appropriate actions may be taken before out-of
specification occurs.

(b) Process Capability Study

A process capability study is used to determine whether a process is
stable and capable. Process capability indices are used to measure
how well the data fits into the specification limits. Frequently used
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process capability indices include Cp and Cpk. Cp is used to evaluate

the variation of the process, and Cpk is used to evaluate the centering
of the process.

It is important for manufacturers to calculate and analyze the values of

Cp and Cpk for their processes and understand the interpretation of
such data. It is recommended that the Cp / Cpk values be targeted at
1.33 or above. Process capability studies assist manufacturers in
determining if the specifications limits set are appropriate, and also to
highlight processes that are not capable. Manufacturers would then
be required to take necessary improvement plans / actions.

5.4 Other types of statistical techniques may also be used, as and when
appropriate in the Product Quality Review. Information derived from such
statistical analysis should be interpreted and conclusions drawn, so as to
ensure that processes are in control and capable.

6.0 CONCLUSION:

Product Quality Review is an important aspect of Good Manufacturing

Practice. It is important for manufacturers and marketing authorization holders
to conduct annual Product Quality Review. The manufacturer and marketing
authorization holder, (where different) should evaluate the results of this
review and an assessment should be made whether corrective and preventive
actions (CAPA) or any revalidation should be undertaken. Reasons for such
corrective actions should be completed in a timely and effective manner.

Where the marketing authorization holder is not the manufacturer, there

should be a technical agreement in place between the various parties that
defines their respective responsibilities in producing the quality review.

The authorized person responsible for final batch certification together with
the marketing authorization holder should ensure that the Product Quality
Review is performed in a timely manner and is accurate. These annual
product reviews should be signed by the authorized person and/or Marketing
Authorization Holder.

REFERENCE

PIC/S GMP Guide (PE-008 and PE-009). Refer to

https://www.picscheme.org/en/publications for the latest version.

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ANNEX-1

In summary, following requirements need to be provided for Product

Quality Review:

(a) Trend analysis of quality control parameters as committed during

marketing authorization application shall be compiled product-wise and
batch-wise,

(b) Market complaints investigation and planned corrective actions.

(c) Product recalls, reasons for recalls and corrective actions.

(d) Returned Goods

(e) Salvaged Goods

(f) Non conformances as per in-house Specifications

(g) Batch failures at various stages of production and their investigations

(h) Changes done in formulation, process and packaging.

(i) Results of Stability studies and retention sample review.

(j) Regulatory changes in Pharmacopoeia / drug act

(k) Changes in Vendor

(l) Changes in facility/equipment

Note: Product Quality Review may be grouped for similar product

(Formulation and Primary Packing is same – brand name or market is
different) and Recommendation (s) shall be made in the report based on the
review, if any change is desired.

END OF DOCUMENT

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Contact Information:

For further information, please contact:

GMP Audit Unit

Audit Branch
Audit & Licensing Division
Health Products Regulation Group
Health Sciences Authority

11 Biopolis Way #11-01 Helios

Singapore 138667
Website: www.hsa.gov.sg

For feedback, please go to:

https://crm.hsa.gov.sg/event/feedback.aspx