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Preparation of Annual Product Review (APR)


Know the procedure to write a perfect Annual Product Review Report (APR) for Pharmaceutical Products.
1.0  The majority of GMP regulatory bodies has made it a mandatory for the companies to have a written procedure for the Annual Product Review process, and recommends review of all the batches that are manufactured in the preceding year from January 1st to December 31st. And the batches include both approved as well as rejected batches.
2.0  The configuration of an annual product review report can vary based on different products and a company’s specific documentation requirements.
3.0  However, a company should follow a standard template to ensure that all required aspects are evaluated.
4.0  As an APR is an evolving document. It should be of few sections with minimal requirements to an elaborate document with addenda containing information or data relevant to the product.
5.0  An Annual product review report should contain the following chapters
5.1  Finished product and Half finished product testing results.
5.2  Critical in-process controls.
5.3  Quality and yield review of failed batches (OOS) & and  CAPA taken 
5.4  Deviations and CAPA taken against each deviation, effectiveness of CAPA on later manufactured batches.
5.5  Review of reprocessed/ reworked batches and reason for reprocess/ rework of the batches.
5.6  Changes proposed, approved and  implemented that are directly or indirectly related to the product, in-case if a change control is raised related to a multi-product facility should be mentioned in the annual product review report of all the products that are manufactured in the facility.
5.7  Validations (Process or Analytical method) if get triggered by the changes made.
5.8  Repacking made
5.9  Regulatory filings made, or updates  made in the existing DMF that owed to the changes made
5.10  Stability studies and any OOT result found at any station, its investigation outcome should also be addressed. Details of add on batches for stability studies.
5.11  Return goods, complaints, recalls, noted for the product.
5.12  Critical equipment qualifications.
5.13  Quality agreements made for the product.
5.14  Effectiveness of CAPA mentioned in the previous year APR.
5.15  Unresolved or open issues of previous year APR.
5.16  Review of starting materials including packaging materials used for the product.
5.17  Retain sample review
5.18  Each numbered sub-section typically should be followed by a comment or observation and finally should have a cumulative summary of the report.
5.19  And the document should finally be reviewed by all the concerned departments, approved by the management and authorized by the quality head.

Related: Importance of APR in Quality Improvements

6.0  Tabulation & Trending of quality parameters:

6.1  Results of all approved batches should be considered for trending (Sigma evaluation), but all batches including failed batches should be considered for tabulating the results.
6.2  The results of all quality parameters should be tabulated against the specifications, and any change made in the specification should be clearly mentioned.
6.3  If a failed batch is considered for trending, then standard deviation between the results (for a particular parameter in the batch failed) increases then eventually, the sigma values also increases, and it further escalates the band between the average and sigma limits.
6.4  Failed batches should be tabulated alongwith.
6.5  Trending of minimum and maximum of all the results, calculation of average of the total results of the batches, calculation of the standard deviation between the batches and calculation of sigma limits should be done for all the quantitative quality parameters.
6.6  A graphical representation of quality trends should be made, graphs
Should be drawn against minimum, maximum, average, standard deviation, ± sigma limits and specification limits.
6.7  The will help in dissecting data and detecting adverse trends wherever applicable.

Related: Procedure for Preparation of APR

7.0  Sigma Calculation:

If measured the same thing many times and draw a straight line for every result or value then a graph forms with bell shape fixed at the tangible point. Then if the width is compared to the height of the bell shaped graph, and it is then called a statistical measurement “standard deviation or sigma” Sigma calculation and evaluation of sigma values obtained are explained with sulphated as an example below.
7.1  Calculation of  sigma (2sigma, 3sigma, 4 sigma or 6sigma)  can be applied to all quantitative quality parameters e.g Assay, LOD, Residue on ignition, impurities etc
7.2  Sigma calculation can be done as follows.
7.2.1  Calculate an average of result of all approved batches (calculation of  average illustrated taking sulphated ash as an example)
S.No
Batch Number
Result
Specification limit
1
XXX12/01
0.05







NMT 0.25%
2
XXX12/02
0.06
3
XXX12/03
0.18
4
XXX12/04
0.06
5
XXX12/06
0.06
6
XXX12/07
0.07
7
XXX12/08
0.06
8
XXX12/09
0.06
9
XXX12/10
0.07
10
XXX12/11
0.19
11
XXX12/12
0.07
12
XXX12/13
0.07
13
XXX12/14
0.19
14
XXX12/15
0.22
15
XXX12/16
0.07
Assume (XXX) batches are produced and approved


Average
0.2+0.4+0.1+0.2+0.2+0.5+0.5+0.5+0.8+0.4+0.7+0.8+1.2+0.9+0.4=XX
XX / XXX= 0.06(Average result)
Note:
Number of digits after decimal point should be as specified in the standard procedures.
7.2.2  Calculate standard deviation for results.
S.No
Batch Number
Result
1
XXX12/01
0.05
2
XXX12/02
0.06
3
XXX12/03
0.18
4
XXX12/04
0.06
5
XXX12/06
0.06
6
XXX12/07
0.07
7
XXX12/08
0.06
8
XXX12/09
0.06
9
XXX12/10
0.07
10
XXX12/11
0.19
11
XXX12/12
0.07
12
XXX12/13
0.07
13
XXX12/14
0.19
14
XXX12/15
0.22
15
XXX12/16
0.07
Assume (XXX) batches are produced and approved
Std deviation (SD)
0.02 (After rounding off)

7.2.3  Calculate 2 x (Multiplied) STD 0.02= ( value obtained for standard deviation) =0.04  (2SD) like wise, SD is to be multiplied with 3 (for 3Sigma) 4 (4Sigma )etc        
7.2.4  Average + 2SD = +2sigma i.e 0.6+ 0.04= 0.1 (+2 sigma value)
7.2.5  Average - 2SD = -2sigma i.e 0.6 - 0.04 = -0.02 (-2 sigma)
7.2.6  Plot a graph for the results obtained, along with ± 2 sigma values.
7.2.7  Following exemplary graph is illustrated against 2,3,4 & 6 sigma values
Chart
8.0  The crux of the APR document is the Conclusions and Corrective Actions/ Recommendations section.
8.1  Identify the batches which fall in the zone away from average and cross ± sigma values.
8.2  Evaluate the batches, for all the possible reasons for sulphated ash being more than the regular trend.
8.3  The reasons for the Sulphated ash being more than the regular trend
may be due to many reasons like i.e
·  Sulphated ash being carried by key starting materials
·  Improper washing
·  Equipment failure during washing
·  Faulty equipment
·  Salts might have form during reaction etc
8.4  If the key starting materials procured from more than one approved vendor and if the batches having result more than the regular trend are manufactured with the key starting material obtained from one particular vendor, then it should be further evaluated through the vendor evaluation.
8.5  Likewise, variation in the parameter which impacts sulphated ash content of the product should be compared with the batches with result near to the average.
8.6  It was a conventional thought that high levels of quality cost more in the long run, but quality is that the best quality does not cost more.     
It actually costs less. Cost-of-quality is actually the cost of deviating from quality–paying for things like variations within specified limits or ranges between batches etc and if that variations can be arrested, then the band between the  average(regular trend) and ±sigma levels can be made narrow and more consistency within the batches.

9.0  Recommendations: 

This section should include summaries of each of the prior sections, and the appropriate corrective/preventive measures necessary for each observation made.

Submitted By.
I.L.Bhavani Chandra
E-mail : lakshmibhavani2102@gmail.com
Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
Email: .moc.enilediugamrahp@ofni Need Help: Ask Question


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