Standard Operating Procedure (SOP) for Annual Product Quality Review (APQR) / Annual Product Review (APR) / Product Quality Review (PQR) / Periodic Product Review (PPR) and How to Prepare standard format for APQR / APR / PQR / PPR
SOP for Annual product quality
review (APQR/APR/PPR/PQR) which is the best tool in pharmaceuticals for
identification of the process/method consistency, the need for product/process,
and method improvement. Here, we are going to see what is APQR/APR/PQR, how to
prepare APQR/APR/PPR/PQR, Content required to prepare standard format of
APQR/APR/PPR/PQR, what is need of APQR/APR/PPR/PQR.
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SOP on Annual Product Quality Review (APQR) / Annual Product Review (APR) / Product Quality Review (PQR) and How to Prepare standard format for APQR/APR / PQR / PPR |
1.0 PURPOSE:
To provide a
written instruction to perform quality review of all drug product,
API and Intermediates of API batches manufactured in one year
(Annually). Collecting, summarizing and reviewing of parameters to study
batches, process variability. To identify and evaluate the need for
product/process/method improvements based on the statistical analysis and
graphical trends to decide the actions.
2.0 SCOPE
Applicable for the data
collection, preparation, and approval of annual product quality review reports.
Covering, finished products, API, and Intermediates of API batches are
manufactured annually.
3.0 RESPONSIBILITY
3.1 Production:
Collect and organize all production data related to the annual product quality review (APQR) includes critical process parameters (controls), manufacturing details (including blending batches) and packing details of batches along with trends.
3.2
Quality Control
Collect and organize Quality Control data related to the annual product quality review includes data of trends, the establishment of trend limits, evaluation of OOT and review of stability data along with trends.
3.3 Quality Assurance:
Collect, organize data and
prepare their graphical trends related to the annual product quality the
review includes batch manufacturing records (BMR), Batch Packing records (BPR),
data related to QC checks, change control, deviation, OOS, OOT, qualification
status, complaints, return, and recall (if any), Review of CAPA. QA assuring
that all the requirements of Annual product quality review (APQR) is fulfilled
and approve the APQR by the head of QA.
Based on the conclusion
provide the recommendations/improvement plan to the concern, departments to
take further actions to improve product/process/method/documentation or need of
revalidation.
3.4 Regulatory Affairs:
Responsible to provide data
to Quality Assurance including product dossier, changes in technical agreement,
additional requirements of technical agreements, variations submitted /
approved / refused.
4.0 DEFINITION
4.1 Annual Product Quality Review
(APQR) / Annual Product Review (APR) / Product Quality Review (PQR)/ Periodic
Product Review (PPR)
Annual evaluation of
product/process/method including comprehensive summary of data of all production (Critical process parameters), analytical (QC test results),
stability, deviations, change controls, out of specification (OOS),
out of trend (OOT), market complaints, product recall, reprocessing,
reworking in case of API or intermediate of API and rejections which measure
the quality standards of each drug product, drug substance.
APQR is an effective quality
improvement tool to verifying the consistency of current process,
correctness of current specifications for both starting materials and finished
product with the graphical trends and to identify product and
process improvements.
APQR is minimize chance of
failure and costs behind that failure.
4.2 Critical Process
Parameter:
A process parameter whose
variability / inconsistency has an impact on a quality attribute and therefore
should be monitored or controlled to produces product of the desired quality.
5.0 PROCEDURE:
5.1 The Annual product
quality review (APQR) report should be prepared annually, considering
batches manufactured from January to December in case of API and Intermediate
product as one year.
5.2 In case of dosage form
(Formulation) one year consider from the first batch manufactured month and as
per this prepare schedule for the products. Mention the reporting month and
next due period in the schedule.
E.g. first batch
manufactured on the 13/03/19 of “X” drug. So, reporting month is Mar-2019 and
due period is Mar-2020. Mar-2019 to Mar-2020 is review period. After completion
of Mar-2020 start to prepare APQR/APR/PQR/PPR.
5.3 APQR dividing
base on -
5.3.1 Type of
product– If organization have multiple manufacturing facility like API,
Intermediate or finished dosage form then prepare separate APQR for API,
Intermediate or finished dosage form.
5.3.3 Brand/drug
name – If manufacturer have more than one brand prepare separate APQR
as per brand name. E.g. if manufacturer have two products “X” and “Y” prepare
two separate APQR.
5.3.2 Type of
dosage form– Prepare separate APQR for finished dosage form like Tablet,
capsule, Cream, Ointment etc.
5.3.3 Strength / Label
Claim– Prepare separate APQR for different strength but same dosage form
and name (brand). E.g. two separate APQR for Allopurinol 100 mg and Allopurinol
300 mg in tablet form.
5.3.4 Market wise –
Some organization prepare APQR market wise. E.g. Europe market, US market,
domestic etc. Consider batches manufactured as per the market.
5.4 The numbering system of
annual product quality review (APQR) report as per below
For API and Intermediates :
APQR or APR or PQR / XXXX /
YYY / ZZ
Where,
APQR denotes Annual Product
Quality Review
APR denotes Annual Product
Review
PQR denotes Product Quality
Review
XXXX denotes Four digits of
current calendar year in which batches were manufactured
YYY denotes
Product Code.
ZZ denotes sequential
number as per product index.
For Example, APQR of year
2020 for Allopurinol USP will have numbering system APQR/2020/ALP/01
For formulations :
APQR or APR or PQR / XX -
XX/YYY/strength of dosage form/ ZZ
Where,
APQR denotes Annual Product
Quality Review
APR denotes Annual Product
Review
PQR denotes Product Quality
Review
XX - XX
denotes last two digits of calendar years in which batches were
manufactured.
YYY denotes product code.
Strength or label claim of
dosage form vary like 5 mg, 10 mg, 1%, 500 mg etc.
ZZ denotes sequential
number as per product index.
For example, APQR report of
Allopurinol 100 mg manufactured in the year 2019 to 2020 should be numbered as
APQR/19-20/ALP/100mg/01.
5.5 Cover page of Annual product quality review (APQR) report
should be prepared.
5.6 Cover page
contains APQR number, product name, strength of product, product code for API and
intermediates, review period and signatures of prepared by Quality
Assurance, reviewed by Production, Quality Control and signed by Unit / plant Head /
highest authority person of plant and approved by Quality Assurance Head.
5.7 All other pages
should be prepared by Quality Assurance and checked by concerned department and sign it.
5.8 Prepare the Annual
product quality review (APQR) report with the following contents and
information: (APQR Contents which include in APQR format)
5.8.1 Introduction
/ Introductory Note:
For formulations,
Annual product quality review (APQR) report should contain generic name, brand
name, dosage form, therapeutic activity or category of the
drug, pharmacopoeial grade, strength of dosage form, pack type, market of
the product and stages involved during manufacturing of the product.
For API, Annual product
quality review (APQR) report should contain drug substance
name, pharmacopoeial grade, therapeutic activity or category of the API
and stages involved during manufacturing of the product.
5.8.2 Action from
previous review (APQR) –
Mentioned the status of
action from previous APQR. If any action still open, then mentioned the details
of that pending action.
5.8.3 Starting Raw
Material (RM) and Packing material (PM)
5.8.3.1 Includes the key
starting raw material used for manufacturing of API and API used in
formulation, excipients, primary packing material, details of approved
vendors, number of batches received, No. of batches Passed and Rejected / OOS,
complaints, Quantitative test results (pH, Assay, total Impurities and
Microbial Count) of Active Pharmaceutical Ingredient (API), Review of
changes to RM / PM specification, wherever applicable.
5.8.3.2 Review of Secondary
Packaging Materials for OOS, rejection or complaints received for related to
the printed packing materials.
5.8.3.3 Prepare trend
for starting raw materials and API, excipient. Prepare trend of primary
packing material should be done similarly considering applicable
parameters.
5.8.3.4 All data collected
from the BMR, BPR, test reports and relevant system.
5.8.4 Manufacturing
details:
5.8.4.1 Annual product
quality review (APQR) should contain the details of number of batches
manufactured, Number of batches packed, Individual batch details contains batch
number, Mfg. date, Exp. Date, batch size and total yield obtained.
Prepare graphical trend for total yield.
5.8.4.2 Prepare the quality
trends for critical In-process parameters
For formulation LOD, friability,
disintegration test, hardness, leak test etc during manufacturing and packing
(critical process parameters varies based on formulation or dosage form). For
API and intermediate pH, conductivity, LOD etc. consider as critical process
parameter. Review of changes
to critical In-process specification, wherever applicable.
5.8.4.3 Graphical trend of
the parameters shall be carried out with clear description of the Lower
specification limits (LSL) and Upper specification limits. (USL).
E. g. Limit is 98% - 100%.
LSL is 98% and USL 100%.
Draw the line for LSL and
USL points in the graph or trend results.
5.8.4.4 Number of
batches rejected, and their investigation, reprocessing or
reworking done for the batches during the year should be mentioned along with
details.
5.8.4.5 For API and
Intermediates, details of Blended batches should be mentioned and evaluated.
5.8.4.6 Details of
utilities like compressed air, nitrogen gas, water etc., if used
during manufacturing should be reviewed.
5.8.4.7 Details of
environmental monitoring condition during manufacturing should be
reviewed (Clean room area details).
5.8.4.8 Report to head QA any abnormal observation found during the assessment of product.
5.8.4.9 All data collected
from the BMR, BPR, test reports and relevant system.
5.8.5 Laboratory Test Results and Trends
5.8.5.1 Review of finished
product / finished API / stability data should be done by trending analytical
(chemical) and physical tests results.
5.8.5.2 Prepare trend
considering analytical (chemical) tests results like water, content
uniformity, LOD, Assay, related substance, Residual solvents, dissolution
test, microbiological examinations etc., and any other
qualitative parameters.
5.8.5.3 Prepare trend
considering physical tests results like particle size, bulk/ tapped
density, specific optical rotation, friability, disintegration test etc. and
any other quantitative parameters.
5.8.5.3 For sterile
(parenteral) plant pH, Assay, foreign matter, clarity of solution, Related
substances, globule size, Extractable Volume, volume in container, color test,
BET, Particulate matter, sterility and their trends.
5.8.5.4 Refer standard
specifications including newly changed specification if any for evaluation of
the quality.
5.8.5.5 Review of
changes to finished bulk specification if any, finished Product
Specification, Stability Studies Specification, Stability Protocol, Active
Pharmaceutical Ingredients Specification, Excipients Specification and
Packaging Material Specification.
5.8.5.6 Included
any rejection of batches (raw material, packing material and finished
product), OOS, OOT and deviation during the review period.
5.8.5.7 If any out
of specification (OOS) / out of trend (OOT) should be documented
during stability study should be mentioned.
5.8.5.8 A summary of all
batches kept for stability of the product included in APQR.
5.8.5.9 Details of reserve
sample mentioned in APQR.
5.8.5.10 Report to head QA
any abnormal observation found during the assessment of product testing
reports.
5.8.5.11 All data collected
from the BMR, BPR, test reports and relevant system.
5.8.6 Deviations
Review
5.8.6.1 Any abnormal
activity or observations made during the review of batch record, product or
process. Prepare summary of investigations conducted on
deviations and effectiveness of resultant corrective and preventive actions (CAPA) taken should be recorded in the Annual product
quality review.
5.8.7 Review of Batch
Failure:
A review of all
batches failing to meet established
specifications and summary of investigations should be
recorded in the APQR. This review should include
5.8.7.1 Summary of number
of failed batches and the root cause for the failure.
5.8.7.2 Summary of
CAPA.
5.8.8 Review of
changes with respect to process, packing, vendor, equipment, facility,
system, test method protocol, specification and documents should be
recorded. Details of change controls along with document reference number
should be recorded.
5.8.9 Review
of qualifications including equipment and utilities like
HVAC, water, steam, compressed air etc should be recorded used for the
product. In case of API, drug substance is manufactured in more than
one area then prepare a separate report of HVAC and water system for each
manufacturing area.
5.8.10 Review of
validation :
5.8.10.1 If any process
validation of the product performed should be recorded. This review should
include summary of the changes made to the process validation.
5.8.10.2 If any analytical
method validation and microbiological method validation performed should be
recorded. This review should include summary of the changes made to the method
validation.
5.8.11 Review
potable water / purified water / WFI/ pure steam:
APQR should cover review
of potable water, purified water / WFI/ pure steam trends.
Decide action plan in case of abnormal observation should be
recorded in the APQR.
5.8.12 Review of
temperature, relative humidity (%RH) and pressure differential records
of product manufacturing, packing and storage area should be reviewed
and recorded in the APQR. Decide action plan in case of abnormal
observation should be recorded in the APQR.
5.8.13 Review
Technical agreements and dossier:
Review of changes to
Technical agreements. Data collect from regulatory affairs (RA) department
regarding technical agreement and dossier. Review of variations submitted /
granted / refused including those for specific country dossier
should be done. Also, technical agreements should be reviewed
for any additional requirements related to APQR.
5.8.14 Review of
commitments:
Any post
marketing commitments during the review period should also be
recorded. This information should be collected from Regulatory Affairs
(RA) department. Regulatory Affairs should collect the same information from
customer or marketing.
5.8.15 Review of
Market complaints, returns or recalls:
5.8.15.1 A review of
quality defects related product returns, complaints, adverse
drug reaction and product recalls and summary of investigations performed at
that time should be recorded in the APQR. This review should include:
5.8.15.1.1 Prepare summary
of batches returned due to potential quality defects, together with the nature
of complaints.
5.8.15.1.2 For formulation,
if any adverse drug reaction reported during the review period then summarize
the action plan. An unexpected adverse reaction is a very serious issue.
5.8.15.1.3 Prepare a summary
of batches recalled and the reasons behind recalls. Mentioned if any
mock recall carried out this review period.
5.8.15.1.4 Prepare summary
of investigation reports prepared for market complaints and CAPA (corrective and preventive action).
5.8.16 Review of
OOT (out of trend):
Prepare a summary of OOT
batches and CAPA taken to prevent a recurrence. The impact analysis should be
performed for out of trend results for all parameters.
5.8.17 Review of
OOS (out of specification):
Prepare a summary of OOS batches and CAPA taken to prevent a recurrence. Impact analysis should be
performed for out of Specification results for all parameters.
5.8.18 Review CAPA:
If any action pending from
the relevant.
5.8.19 External
services review:
Review the quality
attribute of the data in APQR where external services involve in manufacturing
as well as laboratory analysis. Prepare the summary of the service taken. If any
abnormality found then summarize the action plan.
5.8.20 Conclusions:
Decide a conclusion or any
recommendation based on the overall data reported in APQR. Identify
the need of improvement considering process consistency with respect to yield,
quality, stability. Quality Assurance should evaluate the result of review and
assessment should be made whether improvements, any CAPA
or revalidation need.
5.8.21 Issues for Follow
up:
5.8.21.1 If any action is
still open then all open actions cover in this section. The
status of these open actions covers next year's annual product quality
review report.
5.8.21.2 This action
includes but not limit:
Like, quality attributes of
the batches which are manufactured but not released in the period of
review, packing of work in progress (under process) which is produced in
the period of review, complaints, deviations, change controls, OOS, OOT etc
which are not closed in the period of review.
E.g,
1. “A” batch manufactured
as well as packed but not release in market for sell. Cover manufacturing
details in APQR.
2. “A” batch under
manufacturing stage then cover the completed stages of that batch like
granulation, compression, coating etc. as well as packing stage (under
progress).
5.8.22 For sterile
formulations the APQR should cover the review of process impacting
attributes and quality attributes as per below:
5.8.22.1 Review of processing in
aseptic area: It should include result of dispensing, compounding, filtration,
steam sterilization, dry heat sterilization, vial and components washing and
depyrogenation process.
5.8.22.2 Review of media
fill studies: It should cover the review of media fill studies carried out for
specific container closures, equipment, critical environment.
5.8.22.3 Review of gowning
qualification and personnel monitoring results: It should include the review of
gowning qualification and personnel monitoring results for that personnel working in aseptic (Cleanroom) processing area.
5.8.22.4 Review of
microbiological monitoring and non-viable particle count: It
should include the review of microbiological monitoring and
non-viable particle count.
5.8.22.5 Review of
environmental monitoring: It should include the review of environmental
monitoring results and trend during the review period.
5.8.22.6 Review of major
breakdown: It should include the review of major
breakdowns that occurred during processing.
5.8.23 Data
applicable for trend preparation and benefit of the trend:
5.8.23.1 Prepare
trends of all types of data like batch yield, in-process (intermediate) test
results, finished product test results. This all trend beneficial to evaluate
the consistency of the existing process, the suitability of current
specifications for in-process (intermediates), excipients, starting materials,
API, and finished products to identify product and process improvements.
These reviews should be conducted and documented annually to
identify any impact on product quality and CAPA requirements.
5.8.23.2 Minimum 7
batches consider preparing trend. If less than 7 batches are manufactured
during the review period then there is no need to prepare a trend. OOT limit
should be decided by statistical trend evaluation 3 sigma,
4 sigma, 5 sigma (3σ, 4σ, 5σ).
5.8.23.3 If no any batch
manufactured in the review period then APQR prepare and mentioned that their no
batch manufactured during the review period. In such case, previous OOT limit
carries, forward to the next year.
5.8.23.4 If any abnormality
found in the trend limit should be investigated and the same should be
documented in the APQR.
5.8.23.5 Process capability
and performance should be calculated for the trend to evaluate the capability
and the performance of the process. This is calculated based on analytical
results. Process capability and performance calculated as per below:
Where,
Cp – Process capability
Cpk - Process capability
index
Ô¾ – Standard deviation for all batches taken
for Ŝ and c4
Åœ – mean of deviation
c4 – coefficient of
correction
min – Minimum value
consider from the both results
USL – Upper specification
limit
LSL -Lower specification
limit
µ - Mean
5.8.23.5.2 Process Performance (Pp) and Process Performance index (Ppk) - Consider, less than 50 batches.
Where,
Pp – Process Performance
Ppk - Process performance
index
σ – Standard deviation
for all batches
min – Minimum value
consider from both results
USL – Upper specification
limit
LSL -Lower specification
limit
µ - Mean
5.8.23.5.3 Results of Cpk and Ppk
divide in three parts :
·
If Cpk/Ppk ≤ 1 : Cpk/Ppk value obtained less than or equal
to 1 then the process is not capable. So, the assessment required to identify the cause and
eliminate the cause to improve the process/method/specification etc.
·
If 1 < Cpk/Ppk ≤ 1.33 : Cpk/Ppk value obtained in between 1 and 1.33 then the process is capable
to reproduce products within the specification limit. The assessment required based on requirements.
·
If 1.33 < Cpk/Ppk : Cpk/Ppk value obtained in more than 1.33 then the process is excellent. The process is consistent and capable to reproduce results within a predetermined rate.
5.8.24 Some examples of
parameters for which trend limits should be established for formulations are:
- pH
- Tapped Density
- Water Content
- LOD
- Sieve analysis (Particle
size distribution)
- Yield
- Impurity profile
5.8.25 Some examples
of parameters for which alert/trend limits should be established
for API are:
- pH
- Impurity profile
- Residual solvent
- Water content
- LOD
- Assay
6.0 ABBREVIATIONS
API - Active
Pharmaceutical Ingredient
OOS - Out of specification
OOT - Out of trend
CAPA - Corrective ActionPreventive Action
APQR - Annual Product
Quality Review
QA – Quality Assurance
QC – Quality Control
BET – Bacterial Endotoxin
Test
HVAC – Heating, Ventilation
and Air Conditioning
LOD – Loss on drying
7.0 REFERENCES
7.1 Schedule M
7.3 Eudralex Volume 4 Good manufacturing practice
7.4 PIC/S, Guide to Good manufacturing practice for Medicinal products, Part I, Chapter 1
7.5 WHO forty-fifth report Annex 3 point no: 1 Quality Assurance and Annex3 point No. 3.3
7.7 PDA Technical report 60 “Process Validation: A Lifecycle Approach”
7.8 PDA Technical report 59-Utilization of Statistical Methods for Production Monitoring
7.9 ICH Q7“Good Manufacturing Practices for Active Pharmaceutical Ingredients” point - II(E)
8.0 HISTORY
Not Applicable
9.0 ANNEXURES
Not Applicable
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