Annual Product Review

GMP Compliance Workshop 2,


Introduction Review of GMP requirements for Annual Product Review(APR) 2006 GMP Required Contents of APR FDA warning letters Typical contents of SOP for APR Typical contents of an APR Statistical aspects of APR Benefits of Good APR FDA inspections : Expectations for APR Practical issues Conclusion An example of APR
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Introduction
Purpose of APRs
To provide an opportunity to assess the state-of-control of the product and process

The current expectations for APRs

Include data sufficient to allow a determination for the need for changes in drug product specifications or manufacturing or control procedures

APR results follow-up actions relationship

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Review of GMP requirements for APR

21CFR211.180(e)
(e) Written records required by this part shall be maintained so that data therein 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. Written procedures shall be established and followed for such evaluations and shall include provisions for:
(1) A review of a representative number of batches, whether batches approved or rejected, and, where applicable, records associated with the batch. (2) A review of complaints, recalls, returned or salvaged drug products, and investigations conducted under 211.192 for each drug product.
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ICH Q7A
2.50 Regular quality reviews of APIs should be conducted with the objective of verifying the consistency of the process. Such reviews should normally be conducted and documented annually and should include at least: least
A review of critical in-process control and critical API test results; A review of all batches that failed to meet established specification(s); A review of all critical deviations or non-conformances and related investigations; A review of any changes carried out to the processes or analytical methods; A review of results of the stability monitoring program; A review of all quality-related returns, complaints and recalls; and A review of adequacy of corrective actions.
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EU guidelines, Part I
1.5 Regular periodic or rolling quality reviews of all licensed medical products, including export only products, should be 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. Such reviews should normally be conducted and documented annually, taking into account previous annually reviews, and should include at least :A review of critical in-process control and critical API test results;
A review of starting materials and packaging materials used for the product, especially those from new sources A review of critical in-process controls and finished product results A review of all batches that failed to meet established specification(s) and their investigation
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A review of all significant deviations or non-conformances, their related investigations, and the effectiveness of resultant corrective and preventative actions taken A review of all changes carried out to the processes or analytical methods A review of marketing authorisation variations submitted/granted/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 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 The qualification status of relevant equipment and utilities, e.g. HVAC, water, compressed gasses, etc A review of Technical Agreements to ensure that they are up to date
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2006 GMP
2.7.3
No ? . . . . . ?
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Required Contents of APR

Contents Product name and description Time period of batches covered Finished product results In-process product results Process deviations/investigations Rework Batch rejections Stability results Complaints Returned goods Recalls Component results
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21CFR180(e) (o) (o) o (o) o o o (o) o o o

ICH Q7A 2.50 (o) (o) o o o o o o o o

EU Part I 1.5 (o) (o) o o o o o o o o o

06 GMP (o) (o) O O o

Contents Review of NDA etc., Compliance Process changes Test method changes API data OOS results Yields and variances Equipments and utilities Technical agreement Corrective actions Quality Unit approval Management review/approval

21CFR180(e)

ICH Q7A 2.50 o o o

EU Part I 1.5 o o o

06 GMP o o o

(o) (o)

o o o o o (o) (o)

o (o) (o)

o (o)

(o) (o)

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FDA Warning letters

http://www.accessdata.fda.gov/scripts/wlcfm/full_text.cfm?full_text=annual+product+review
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Kos Pharmaceuticals Inc., Dec 29,03 Failure to follow written procedures for Annual product review[21CFR211.180(e)
Your firms QCU failed to follow established written procedures for conducting Annual Product Reviews(APR). Specifically, the APR for your Niaspan product was approximately 13 months overdue even though your SOP #QA-450-00 states that the review will be performed at least annually.
http://www.fda.gov/foi/warning_letters/g4502d.htm

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Applied Laboratories Inc., Nov 19,03 #2 Management Representative

A memo of 9129103 designates Mr. Moravec to be Head of the Management Review Team, and Procedure No. 002SOPO204.00, Revision No. 03,was amended to define the Management Representative to be the Head of the Management Review Team. The changes in the revised procedure do not include an outline of the specific duties to be handled by the Management Representative/Head of the Management Review Team. The procedure also references two CFR regulations that are NOT correct for either the Management Representative, 21 CFR 820.20(b)(3), or for the drug Annual Product Review, 21 CFR 211.180(e).
http://www.fda.gov/foi/warning_letters/g4408d.htm
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Pharma Fab, Jun 15, 04 FDA-483

7. Failure to review complaints as part of your annual product review in order to evaluate the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures [21 CFR 211.180(e)(2)]. For example, your firm lacks documentation to demonstrate a comprehensive annual evaluation of the Adverse Event Log to determine significant trends as directed by SOP #QA-1091-00. Title: Adverse Event Reports.
http://www.fda.gov/foi/warning_letters/g4897d.htm

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Typical contents of SOP for APR

1. 2. 3. 4.

Regulatory Reference Purpose Scope Role and Responsibility

4.1 4.2 4.3 4.4 Quality assurance Production Quality control Regularly affairs and clinical safety

5.

Procedure
5.1 APR framework 5.2 APR tools 5.2.1 Trend analysis 5.2.2 Mean charts

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5.3 APR report checklist 5.3.1 Recommendations from prior APR report 5.3.2 Batches manufactured 5.3.3 Batches rejected 5.3.4 Batches reworked/reprocessed 5.3.5 Deviations, OOS results 5.3.6 Environmental monitoring data 5.3.7 Product specification/Method changes 5.3.8 Retain samples 5.3.9 Changes effected(change control) 5.3.10 Analytical data 5.3.11 Validation review 5.3.12 Recalls 5.3.13 Customer complaints and returns
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5.3.14 Adverse drug events(US marketed products only) 5.3.15 Inspections from any official inspectorate 5.3.16 New recommendations
6. 7.

Definitions Attachment

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Typical Contents of an APR

Time period covered()
All batches manufactured or dispositioned(released or rejected) during a specific period, usually 1 year

Production description()
A detailed description of the product For example, product, packaging configurations, and reference the control numbers in use to identify the formulation in use

Summary of review( )
To provide an overview of any key observations made For example, a large number of deviations, any unexpected results
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Recommendations and/or corrective actions( )

For focusing on key aspects and saving ones time, highlight issues and concerns early, esp., management,

Finished products results( )

A representative number of batches all batches produced all key analytical and physical parameters must be included To provide clues regarding the integrity and consistency of the process In-process analytical/physical results and critical processing parameters
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In-process results( )

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Deviations/Investigations/Rework(// )
All product or process deviations, investigations conducted for deviations or nonconforming situations, and any rework conducted All cases must be included highlight concerns and provide evidence

Stability results( )

A key indicator of the control and consistency of any process Should list any stability trends, deviations, or shifts A summary of all product complaints Should additional review of any trends or problematic batches
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Complaint results( )

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Returned goods()
A summary of all product returned for quality concerns Provide valuable information not normally evident to the quality unit regarding product concerns or problems

Recalls()
The reasons and corrective actions taken

Conclusions()
Process in control
No abnormalities within sets of data and confirms that the process continues to function as validated

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Actions recommended
Some recommended actions should be considered, but the process is essentially functioning as designed and validated The process continues to operate in a state-of-control

Corrective actions required

The need for immediate actions or corrections The process is not operate in a state-of-control

Recommendations for changes with responsibilities and a timeline for corrective actions
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Approvals()
Appropriate approvals by representatives from production, QC, QA, and others etc

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Statistical aspects of APR

Data can be presented in a variety of ways, tabular or graphical form. Mean, standard deviation, relative standard deviation, process capability, control chart, normality test, etc Spreadsheet vs Software
Microsoft Office Excel MINITAB release 14

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Typical tabular form

A B F 95.0 105.0 2.31 3.15 97.1 97.6 98.7 99.7 100.3 0.59 Cpk Cp -3s -2s Mean +2s +3s s 97.7 100.0

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Typical graphical form

105.0 104.0 103.0 102.0 101.0 100.0 99.0 98.0 97.0 96.0 95.0 4995 5000 5005 5010 5015 5020 5025 5030 5035

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Microsoft Office Excel

MINITAB release 14

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Test results of XYZ tablet

Batch No.
5001 5002 5003 5004 5005 5006 5007 5008 5009 5010 5012 5011 5013 5014 5015 2006.06.26

97.6 98.9 99.5 99.7 100.4 100.4 100.7 99.1 98.9 97.7 98.9 99.4 98.0 98.0 98.0

3.7 3.1 3.6 4.3 3.8 4.2 5.5 5.4 4.5 4.1 5.3 6.4 3.2 3.4 3.6

98.7 99.4 98.9 98.4 98.7 98.9 98.7 97.8 98.5 98.1 98.6 98.4 98.2 99.5 98.7

Batch No.
5016 5017 5018 5019 5020 5021 5022 5024 5023 5025 5026 5027 5028 5029 5030

97.1 98.1 97.0 97.2 96.6 97.3 97.6 96.0 98.1 97.4 99.7 98.3 99.4 97.5 96.3

3.6 3.1 3.1 5.5 4.0 2.9 5.3 4.3 4.9 4.9 2.7 3.1 4.5 3.1 2.3

98.1 99.7 99.9 97.7 98.0 98.8 98.4 98.1 98.1 98.4 99.2 98.8 98.4 98.9 100.0 28

GMP Compliance Workshop

Microsoft Office Excel

chart
Mean Max Min SD() RSD Mean+3 Mean-3 98.3 100.7 96.0 1.24 1.26 102.0 94.6 4.0 6.4 2.3 1.01 24.85 7.1 1.0 98.7 100.0 97.7 0.59 0.60 100.4 96.9

105.0 104.0 103.0 102.0 101.0 100.0 99.0 98.0 97.0 96.0 95.0 4995 5000 5005 5010 5015 5020 5025 5030 5035

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MINITAB release 14
2006-06-19 9:02:25

Minitab . F1 . : 'E:123456~1~1XYZ TABLET.MPJ' : ABC tablet : SE TrMean CoefVar 98.667 0.108 98.638 0.590 0.349 0.60 2960.000 97.700 Q1 Q3 IQR 98.175 98.650 98.900 100.000 2.300 0.725

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MINITAB release 14

Anderson-Darling A- P- N 1 3 98.446 0.58 0.118 98.667 0.590 0.349 0.671218 0.014558 30 97.700 98.175 98.650 98.900 100.000 98.887 98.800 0.794

97.8

98.4

99.0

99.6

95%

5% p- 0.118 0.05
95%
98.4 98.5 98.6 98.7 98.8 98.9

95% 98.400 0.470 95%

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 I-M R
UCL=100.253 100

99

_ X=98.667

98

97 1 4 7 10 13 16 19 22 25 28

LCL=97.080

2.0 1.5 1.0 0.5 0.0 1 4 7 10 13

Action limit(3) 1 UCL : 100.253 LCL : 97.080

UCL=1.949

__ MR=0.597

LCL=0 16 19 22 25 28

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LSL
LSL 95 * USL 105 98.6667 ?N 30 () 0.528858 () 0.595454

USL
() Cp CPL CPU Cpk CCpk 3.15 2.31 3.99 2.31 3.15

Pp PPL PPU Ppk Cpm 2.80 2.05 3.55 2.05 *

96.0
PPM?<?LSL 0.00 PPM?>?USL 0.00 PPM?Total 0.00 PPM?<?LSL 0.00 PPM?>?USL 0.00 PPM?Total 0.00

97.5

99.0

100.5

102.0

103.5

105.0

PPM?<?LSL 0.00 PPM?>?USL 0.00 PPM?Total 0.00

(Cpk) 2.31

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Benefits of Good APR

SE7EN key benefits or purposes for effective APRs
Assess needed changes in product specifications Assess needed changes in manufacturing or control procedures Determine if validation or revalidation is needed Identify product improvement or cost reduction opportunities Confirm change control systems Provide a preparation tool for inspections Communicate product and process status to management
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FDA inspections : Expectations for APR

Develop a comprehensive SOP Follow the SOP Include all required and expected elements in the APR Identify and implement corrective or improvement actions Follow-up on actions Assure that the quality unit reviews and approves the APR Involve management in the process

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Practical issues
APR T/F ? Report ? Data ! system (, ERP)! Critical parameter routine monitoring system tool !? , Process validation ! follow-up action Report multiplayer?

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Conclusion
APRs
Provide compliance to GMP regulations Provide an effective means for evaluating and implementing improvements to your products Reference tool : problem resolution activities, R&D, reference for future Quality improvement tool : improve a process or cost reduction Management tool : provide annual feedback and define how well process operate

Critical aspects

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An example of APR

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Thank you for attention

References
http://www.ivthome.com/free/gxpv6n2pg6.ht m http://www.accessdata.fda.gov/scripts/cdrh/c fdocs/cfCFR/CFRSearch.cfm?fr=211.180 PQM 2005 , 2005.05.24

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