Product quality review

Presentation prepared by “Drug Regulations”
a not for profit organization.
www.drugregulations.org

 This presentation will cover
◦ Regulations
◦ Objectives
◦ Comparison of objectives: WHO/EMA / FDA/ ICH
◦ How to perform
◦ How to perform: Comparison of WHO/EMA/FDA/ICH
◦ Procedure for review :Comparison of WHO/EMA/FDA/ICH
◦ Data Analysis
◦ Responsibility : Comparison of WHO/EMA/FDA/ICH
This presentation has been prepared form publicly available material on the
World Wide Web.

 Required to be completed annually
 Incorporates a review of multiple aspects
 Determines impact on the quality of the finished
product and active ingredients.

 Powerful quality management tool
 Covers all aspects of the supply chain
◦ Starting materials
◦ Process
◦ Process environment
◦ Process output (product)

 WHO
◦ Good manufacturing practices for pharmaceutical products: main
principles , Annex 2 , 1.10
 EMA – Part 1 of EU GMP , Chapter 1, 1.10
◦ Draft published in November 2005
◦ Effective from January 2006

 FDA: 21CFR 211. 180(e)
◦ Requirement published in September 1978
◦ Effective March 1979
◦ Commonly referred as “Product Annual Review”.
 ICH : Q7A – section 2.5 and 12.6
◦ Adopted by FDA in August 2001
◦ Adopted by EMA in October 2005 , part II EU GMP covering
Basic Requirements for Active Substances used as starting
materials.

Objectives EMA FDA Q7A WHO
Verifying the consistency of the
existing process
Specified x Specified Specified
Verifying the appropriateness of
current specifications for starting
materials
Specified x x Specified
Verifying the appropriateness of
or need for change in current
specifications for Finished
Products
Specified Specified x Specified
Need for changes in
Manufacturing or control
procedure
x Specified x x
To highlight any trends Specified x x Specified

Objectives EMA FDA Q7A WHO
To identify product
improvements
To identify process
improvements
To evaluate the need for
Corrective and preventive
actions
To evaluate the need for
Revalidation of production
process

 Normally annually
 Deviation from p.a. basis possible but has to be
justified(cf. objectives of the PQR)
◦ e.g. when number of batches produced is too small for trending
 Periodic or rolling - both acceptable
 Previous reviews should be taken into account

 Procedure should be described in an SOP in order to
ensure that:
◦ Report is available soon after end of respective period
◦ All batches are considered (no gaps)
◦ Report concludes with assessment, whether / to what extent
CAPA or revalidation should be undertaken

 Especially those from new sources.
 Summary of all batches received in a year and
their approval status;
 Summary of the suppliers/manufacturers of the
materials;

 Compilation and analysis of
 Analytical tests for key quality attributes
 Description
 Identification
 Loss on drying/water content by Karl Fisher
 Particle size
 Related substances
 Assay;

 Compilation and analysis of
 Certificate of analysis (COA) results obtained from
Supplier/manufacturer
 Details significant deviations observed such as rejection
of vendor lots

 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

 Finished product test results
 Description/appearance
 Identification
 pH
 Loss on drying/Water by KF
 Viscosity
 Dissolution test
 Impurities and related substances
 Degradation product (if any) and
 Assay.

 Summary of the number of failed batches/products.
 Identify the batches that failed specifications
 root cause for this failure, if identified
 Summary of the reasons for failure
 Assignable causes
 Non-assignable causes
 Summary of the completed investigation report(s)
 Corrective actions taken.

 Significant deviations
 Non-conformances
 Related investigations
 Effectiveness of resultant corrective and preventive actions taken
 Causes of the non-conformance, sorted based on data trending
 Trend analysis of corrective and preventive actions (CAPA) taken

 All changes carried out to the processes
 Mixing time
 Blending time
 Drying time
 Coating process
 Compression speed/time
 Filling speed
 Review/report of the impact of the changes on the quality of the product.

 All changes carried out to the analytical methods
 Solvents
 Buffers
 Reagents
 pH
 Composition of mobile phase
 HPLC/GC method parameters
 i.e. flow rate, temperature, wavelength, run time, and change of HPLC/GC column
 Review/report of the impact of the changes on the quality of the product.

 Marketing Authorization variations submitted/granted/refused, including those
for third country (export only) dossiers.
 Number of products registered with local and overseas authorities that were
covered in the review document, if grouping by product type are done.
 Changes made to the product specification and their status of approval.
Document the regulatory decision.
 Number of products submitted but not approved/refused by the local and
overseas authority

 Results of the stability monitoring programme and any adverse trends.
 Number of batches included for stability studies during the review
period and the reasons for their selection.
 Stability study report and results, i.e.
 Out of specifications for each conditions (real time/long term and
accelerated studies),
 Review of the results obtained for stability indicating analytical tests.

 Quality-related product returns, complaints and recalls
 Investigations performed at the time.
 Batches returned due to potential quality defects, together with the
reasons.
 Market complaints received in a year, together with the nature of
complaints.
 Batches recalled, together with the reasons.
 Investigation reports prepared following market complaints and the
actions taken to prevent recurrence.

 Summary of all corrective actions from previous product quality review
reports
 Implementation status of each of the corrective actions
 Their effectiveness in addressing the problems.

 FOR New marketing authorizations and variations to marketing
authorizations,
 Review of post-marketing commitments.
 Changes, in terms of the specifications
 registered with drug regulatory authority, including overseas drug
regulatory authorities.
 Post-marketing commitments
 Review of status of these commitments

 The qualification status of relevant critical equipment and
utilities,
 e.g. HVAC, water, compressed gases, etc.
 Number of equipment / instruments
 production and laboratory department.
 Qualification/re-qualification status of equipment / utilities
 production processes and QC laboratory

 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.

 Review of Technical Agreements to ensure that they are up to date.
 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.

 Review of written contract covering the technical requirements
between contract giver and contract acceptor (if any).
 A summary report would be sufficient.
 Determine whether there is a need to revise/update the technical
agreements.

Items for Review EMA FDA Q7A WHO
A review of a representative
number of batches, whether
approved or rejected, and, where
applicable, records associated
with the batch
X Specified X x
Review of starting /packing
materials especially from new
sources
Specified X X Specified
Review of supply chain
traceability for active substances
Specified X Specified Specified
Review of critical in-process &
finished product results.
Specified X Specified
Review of all batches that failed
to meet specifications & their
investigations

A review of all significant
deviations or non-conformances,
their related investigations, and
the effectiveness of resultant
corrective and preventive actions
taken
A review of all changes carried
out to the processes or analytical
methods
A review of Marketing
Authorisation variations
submitted, granted or refused,
including those for third country
(export only) dossiers.
A review of the results of the
stability monitoring programme
and any adverse trends.

A review of all quality-related
returns, complaints and recalls
and the investigations performed
at the time.
Specified Specified
Investigations
under under
211.192
Specified Specified
A review of adequacy of any
other previous product process
or equipment corrective actions
For new marketing
authorisations and variations to
marketing
authorisations, a review of post-
marketing commitments
Review of qualification status of
relevant equipment and utilities,
e.g. HVAC,
water, compressed gases, etc
A review of any contractual
arrangements as defined in
Chapter 7 to ensure that they are
up to date

Procedure EMA FDA Q7A WHO
Frequency Annually Annually x Annually
Account for previous
reviews
Should be taken into
account
X X Should be taken
into account
Groupings by product type Specified X X Specified
Products All authorised medicinal
products, including
export only products,
X X All products
including export
only products.
Written Procedure Not specified Specified. X Specified
Written Report Specified X Specified Specified
Completion of corrective
action in a timely manner
Ongoing management
review of follow up actions
as part of self inspection
specified X x Specified

 Should not be a meaningless listing of data.
 Should review of all required components including:
 Appropriate summary; evaluation and interpretation of the
information available on the manufacturing process.
 Should have the capability of detecting long term trends.
 Should not be considered in isolation and should be linked to
the findings of previous reviews.

 Controlling and improving processes and quality
 Highlighting areas for focusing resource thereby:-
◦ Decreasing risk of out-of specification results.
◦ Decreasing downtime and increasing productivity.
◦ Decreasing the risk of product recall.
◦ Enhancing regulatory compliance.
◦ Improving communication across all areas including production,
engineering, quality and regulatory functions.

 Enhancement of visibility where manufacturing
operation are contracted out
 (production, distribution, testing etc).
 Improvement of product quality
 Contributing to the protection of public and animal
health.

 Trend data using appropriate statistical techniques
to draw the conclusions.
◦ Time series plots
◦ Control charts
◦ Process capability study

 Facilitates corrective or preventive action should
the process be out of control.
 Determines if
 (i) the process is in control; and
 (ii) the process is capable.

 Establishes control limits through trending
 Determines the appropriateness of the specifications
for starting materials and Finished products.
 Determines trends to identify product & process
improvements.
 Trigger to initiate action if process is out of control or
has low capability.

 Shewhart Control Charts.
 X-bar charts, R-charts and Moving Range charts etc.
 Enables
 Determination of upper and lower control limits
 Identification of trends
 upward trend of data, shift in mean etc
 Appropriate actions may be taken before out-of
specification occurs.

An Xbar chart is used to observe and evaluate the behavior of a process over
time and take corrective action if necessary. The chart plots the average values of
each of a number of small sampled subgroups. It is usually plotted in conjunction
with the R (Range) Chart or the s (Standard Deviation) Chart
A. Sample Mean
B. Sample Number
C. Lower Control Limit (LCL)
D. Process Average
E. Upper Control Limit (UCL)
F. Plot of the individual sample
Means vs sample number.
Out of Control Point

A = Sample Range –
B = Sample Number C=
Lower Control Limit (LCL)
D. Process Average
Range –
E. Upper Control Limit
(UCL) –
F. Plot of the Range
values vs sample number.
The R Chart plots the range values, or the difference between the highest
and lowest values, for a series of subgroups.

A. Sample StDev –
B. Sample Number –
C. Lower Control Limit (LCL) –
D. Process Average –
E. Upper Control Limit (UCL)
F. Plot of the sample Standard
Deviation values vs sample
number.
The chart plots the standard deviation of each of a number of sampled
subgroups

 Indices measure how well the data fits into the specification
limits.
 Frequently used process capability indices include Cp and
Cpk.
 Cp is used to evaluate the variation of the process.
 Cpk is used to evaluate the centering of the process.
 Normally the Cp / Cpk values be targeted at 1.33 or above

USL = Upper Specification Limit, LSL =
Lower Specification Limit.

 Cp and Cpk are statistical tools
 Ensures that a production process has met the
specification limits defined for a particular process or
products.
 Cp measures the process capability with respect to its
specification using Upper Specification Limit (USL)
and Lower Specification Limit (LSL)

 Cpk measures the process variation with respect to its sample mean,
which is also considered to be the process mean.
 Process capability is determined by taking periodic samples from
process under controlled conditions and calculating its standard
deviation and sample mean.
 Standard deviation determines how far a sample is from the sample
mean
 sample mean is the average of the samples taken under consideration.

Cp < 1: The process output
exceeds specifications. The
process is incapable.
Cp = 1: The process barely
meets specifications. There is a
probability that at least 0.3%
defects will be produced and
even more if the process is not
centered.
Cp > 1: The process output falls within specifications, but, defects might be
produced if the process is not centered on the target value.
Cp = 2: Represents the short-term objective for process capability. Since Zst = 3
x Cp, we achieve 6 sigma when Cp = 2.

Cpk = Cp: The process mean is
on target.
Cpk = 0: The process mean falls
on one of the specification limits,
therefore, 50% of the process
output falls beyond the
specification limits.
Cpk < -1: The process mean is completely out of the specification limits,
therefore, 100% of the process output is out of specification limits.

 Other types of statistical techniques may also be
used
◦ Proper Interpretation of statistical analysis
◦ Conclusions to be drawn
◦ Determine whether the processes are in control and
capable.
◦ Initiate action if process are out of control

Procedure EMA FDA Q7A WHO
Responsibility to ensure
accurate & timely review
Contract manufacturer
responsibility

 Important aspect of Good Manufacturing Practice.
 Manufacturer and marketing authorization holder, (where
different) should evaluate the results of this review
 Assess if (CAPA) is required
 Assess if revalidation is required
 Complete corrective actions in a timely and effective
manner.

 If M A holder is not the manufacturer, have a
technical agreement to define responsibilities
 Authorized person and marketing authorization holder
should ensure that the Review is performed in a timely
manner and is accurate.
 Reviews should be signed by the authorized person
and/or Marketing Authorization Holder.

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