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 the need of APQR/APR/PPR/PQR.

SOP on Annual Product Quality Review (APQR) / Annual Product Review (APR)

1.0 PURPOSE:

To provide a written instruction to perform quality review of all drug products, API and Intermediates of API batches manufactured in one year (Annually). Collecting, summarizing and reviewing 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. 

3.1 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.. 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 Anuual Product Quality Review (APQR) / Annual Product Review (APR) / Product Quality Review (PQR) / Periodic Product Review (PPR)

Annual evaluation of product/process/method including a 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 “A” 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 facilities like API, Intermediate or finished dosage form then prepare separate APQR for API, Intermediate or finished dosage form.

5.3.2 Brand/drug name – If manufacturer have more than one brand prepare separate APQR as per brand name. E.g. if manufacturer have two products “A” and “B” prepare two separate APQR.

5.3.3 Type of dosage form– Prepare separate APQR for finished dosage form like Tablet, capsule, Cream, Ointment etc.

5.3.4 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.

5.3.5 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 / AAAA / BBB / CC

Where,

APQR denotes Annual Product Quality Review

APR denotes Annual Product Review

PQR denotes Product Quality Review

AAAA denotes Four digits of current calendar year in which batches were manufactured

BBB denotes Product Code.

CC 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 / YY – YY/PPP/strength of dosage form/ ZZ

Where,

APQR denotes Annual Product Quality Review

APR denotes Annual Product Review

PQR denotes Product Quality Review

YY – YY denotes last two digits of calendar years in which batches were manufactured.

PPP 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:

5.8.23.5.1 Process Capability (Cp) and Process capability index (Cpk) – Consider, more than 50 batches.

 

Where,

Cp – Process capability

Cpk – Process capability index

Ծ – Standard deviation for all batches taken for Ŝ and c4

Ŝ – 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

7.2 21 CFR211.180 (e)

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

7.6 Process Validation: General Principles and Practices. January 2011,Good manufacturing practice –Revision 1

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

FAQ: