Annual Product Quality

Review

(APQR)

Dr. A. Amsavel

“You tell me, … and I forget.

You teach me,… and I remember.

You involve me,… and I learn.”

- BENJAMIN FRANKLIN

Introduction

• Quality Unit• APQR

– Requirement– Responsibility– Documents and data required– Preparation and evaluation – Conclusion

ICH Q7- 2.0 Quality Management

• 2.1 Principles– Define Responsibilities & Authorities

• 2.2 Responsibilities of Quality Unit (s)– Quality Control / Assurance, Independent of Production

• 2.3 Responsibilities of Production activities

• 2.4 Internal Audits (self Inspection)

• 2.5 Product Quality Review

Quality Assurance responsibilities :

• Releasing or rejecting all APIs and intermediates for outside use

• Establishing a system to release or reject raw material intermediates, packaging and labelling materials ;

• Reviewing completed batch production and laboratory control records of critical process steps

• Making sure that critical deviations are investigated and resolved;

• Approving all specifications and master production instructions;

• Approving all procedures impacting the quality of intermediates or APIs;

• Making sure that effective systems are used for maintaining and calibrating critical equipment ;

Questions?

• What is an annual product review?• What is the objective of APR? • Who is responsible?• What is procedure & reference for APQR? • What are the data must be presented in an

annual product review? • How should an annual product review be

organized? • Review and conclsion

Annual Product Review - WHAT

Directive Statement:An Annual Product Review must be conducted for

each commercial product. The purpose of this annual review is to verify the consistency of the process, to assess trends, to determine the need for changes in specification, production, manufacturing and/or control procedures and to evaluate the need for revalidation.

Annual Product Reviews (APRs) are important for communication between manufacturing, quality and regulatory Affairs, to enable quality improvement processes. Content and management of Annual Product Reviews must be established according to this directive.

Reference - APQR

• US FDA –Published in 1978 GMP Guideline which was included to review the quality standards

• All GMP Guidelines refer the requirement of APQR– CFR 211.180 (e):– ICH Q7– EU GMP– WHO- GMP

Requirement of APQR

• In USA - "Annual Product Review“• In Europe, the EU GMP Guideline uses the

term "Product Quality Review".• Requirement or expectations are almost same• APQR should be conducted for all commercial

product. • APQR should confirm the State of Control

The US Requirements: 21 CFR 211.180 (e)

• US FDA objectives for performing the APR are to determine the need to make changes in the – manufacturing process, – the manufacturing controls (e.g., in-process testing and

monitoring), evaluate the needs for revalidation and – product specifications.

to evaluate the compliance status of the manufacture and to identify areas of improvement

A review of a representative number of batches, whether approved or rejected, and records associated with the batch

A review of complaints, recalls, returned or salvaged drug products, and investigations conducted under Sec. 211.192 for each drug product.

The Requirements for APIs in ICH Q72.5 Product Quality Review

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:

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

The Requirements for APIs in ICH Q7

2.5 Product Quality Review

2.51 The results of this review should be evaluated and an

assessment made of whether corrective actions or any

revalidation should be undertaken. Reasons for such corrective

action should be documented. Agreed corrective actions should

be completed in a timely and effective manner.

The EU Requirements for PQR (1)

• EU Guidelines to Good Manufacturing Practice ; Medicinal Products for Human and Veterinary Use ; Part I ; Chapter 1 Quality Management (issued on 25 October 2005)

Product Quality Review

1.5 Regular periodic or rolling quality reviews of all licensed medicinal products, including export only products, should be conducted with the objective of verifying consistency of the existing process, the suitability 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 reviews, and should include at least:

The EU Requirements for PQR (2)• 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.• 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.

The EU Requirements for PQR (3)• 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 gases, etc

• A review of Technical/Quality Agreements to ensure that they are up to date.

Benefit or use

• Decrease the risk of out-of-specification results

• Minimize the risk of rework/reprocessing

• Decrease downtime

• Increase productivity

• Decrease the risk of product recalls

• Meet all regulatory commitments/requirements

• Improve communication between production, engineering, quality and regulatory functions

Responsibilities

• It is responsibilities of QA• Establish an SOP with responsibility and process of APQR • Individual departments have to provide the data and

participating in the APQR process. • Reviews should normally be conducted and documented• The Quality Unit, as the central position, should request this

review and coordinate the necessary work. Can develop format/ check list to get information.

• Other departments, like Production, Engineering, Maintenance, Purchase, etc. are also need to be involved.

• Senior Quality Management must approve the APQR.

Requirements • Written procedures shall be established and it must be followed ;• APQR must cover a one-year rolling period, but does not have to

coincide with a calendar year• The review should normally be completed within 60 calendar days• APQR for all products manufactured• In case product not manufactured in the year of review , shall

review stability and complaint, Recall & returns etc.• APQR must be prepared for each water quality grade produced• For critical utilities it is recommending either to perform a separate

APR or to include a specific chapter in the APR.• APQR must include all batches of product (accepted /rejected

/destroyed )• APQR must address the assessment of data, documents and

electronic records reviewed

Preparation

• Appropriate statistical tools may be used to assess process capability when data from a large number of batches is being reviewed.

• Where the data concludes that there is a drift in process capability , actions should be determined to evaluate the causes and improve performance in the forthcoming review period.

• The review of all batches which fail to meet specification and the review of critical deviations

• should look specifically at recurring causes and identify appropriate actions to reduce the frequency and improve performance.

Corrective action

• Equipment not functioning correctly or in need of maintenance or replacement.

• Inadequate batch instructions or training of operators.• Process parameters so tightly defined that the equipment is

not capable of routinely• achieving the acceptance criteria.• Inhomogeneous product or inadequate sampling procedures.• Poor quality raw materials or lack of control of raw material

suppliers.• Retest period or expiry date • Revalidation, requalification

Review and document

• Review must include, at a minimum• Review of any recommendations and actions taken from

prior report• "Basic statistics"

Number of batches manufactured, including partially completed batches and corresponding yields

Number and percentage of batches rejected, reworked or reprocessed and related reasons

Critical in-process controls, finished product results and critical API test results

Review and document• Review of "deviations from the validated state“

A review of all batches that failed to meet established specification(s) and

their investigation

Significant/critical deviations, Out of Specification Results and related failure

investigations (review of adequacy and effectiveness of corrective and

preventative actions taken)

Product quality complaints &Product Recalls

Quality related issues for returned, and/or salvaged goods

Changes effected (change control) and variations during the period (e.g.

process, suppliers, equipment, critical utilities)

Changes of product specifications or methods (e.g. analytical changes, and

results)

Review and document• Effectiveness of implementation of CAPA• out of calibration results;• Process and analytical equipment retirement;• Water quality ;• Validation carried out in process and analytical method;• results of the stability monitoring program;• Environment monitoring (bio-burden) in the clean room;• Yield output variations;• return goods and salvage of product;• Retain sample • Regulatory issues if any

Review and document• Trend Analysis

Trend analysis on key in-process and release testing with graphic representation and basic statistics recommended

A review of the results of the stability monitoring program and trend analysis on stability data

• Observations/Recommendations an conclusion Report the review observations. Recommendations from this review

• The results of the APR must be evaluated and an assessment made whether corrective or preventive action or any re-validation is necessary.

• A conclusion statement must be written to assess if the product consistently meets its quality attributes, and if not, what actions need to be taken.

• Rationale for such CAPAs must be documented.

Data collectionS.No

Batch number

% MC

%Assay

Related substances by GCVolatile substances

by GCImp-A

Imp-K Sum of

impurities Methanol

Toluene

54 XXYYZZZ 0.28 100.1 0.06 0.00 0.00 0.10 0.00

55 XXYYZZX 0.24 100.0 0.05 0.00 0.00 0.04 0.00

56 XXYYZZY 0.31 99.9 0.06 0.00 0.00 0.02 0.00

Mean 0.27 100.0 0.06 0.00 0.00 0.04 0.00Standard Deviation 0.05 0.1 0.01 0.01 0.00 0.03 0.01Minimum 0.16 99.7 0.05 0.00 0.00 0.00 0.00Maximum 0.35 100.3 0.07 0.04 0.00 0.13 0.04RSD 18.37 0.1 10.38 529.84 0.00 77.93 366.42Natural specification Limit

0.12 99.6 0.04 -0.02 0.00 -0.06 -0.03

µ ± 3σ 0.41 100.4 0.07 0.02 0.00 0.14 0.03

Specification RangeNMT 0.4%

98.0-102.0 %

NMT 0.1%

NMT 0.1%

NMT 0.5 %

NMT 0.3%

NMT 0.2%

Trend Chart

Upper limit

% Assy

Mean

: 99.8

Standard Deviation

: 0.1

Minimum

: 99.5

Maximum

: 100.1

RSD

: 0.1

Natural specification Limit

Lower Limit

: 99.4

( µ ± 3σ)

Upper Limit

: 100.2

Specification or Parameter Range

:

98.0-102.0 %

94

96

98

100

102

104

106

1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61 64 67 70 73 76 79 82 85

% A

ssa

y

Batch Number

XXXXXX Batch Vs % of Assay

USL

UNSL

MEAN

Assay

LNSL

LSL

Trend Chart

Process capabilityProcess consistency can be established by Cpk Process capability index (Cpk) can be calculated as below;

SU - SL

CPk = --------- 3σ

One sided specification SU – x x - SL

CPk = ---------- or CP = --------- 3σ 3σ

1.33 ≤CPk Satisfiable enough

1.00 ≤CPk < 1.33 Adequate

CPk < 1.00 Inadequate

Process consistency- Yield

Yield range : 100 -120 kgStd deviation : 3.0Mean : 110kg

20Cpk = ------------ = 1.11

6*3.0After change made in the process

Std deviation : 2.2 and mean 112 kg 20

Cpk = ------------ = 1.515 6*2.2

Normal distribution

Normal Distribution:µ ± σ = 68.3%µ ± 2σ = 95.4%µ ± 3σ = 99.7%

Stability trend

%AssayMean : 99.7%Standard Deviation : 0.1%Minimum : 99.4%Maximum : 99.9%RSD : 0.1%

Natural specification LimitLower Limit

: 99.3%

( µ ± 3σ)Upper Limit

: 100.0%

Specification or Parameter Range : 99.0 % to 100.5 %

Review of documents & systemData collection and review

• Manufacturing instructions and packaging procedures • Changes compared to the previous year • Validation status following a change

• Batch production records• Actual values for process parameters during production• IPC data • Deviations • Yield • Raw materials

• Test procedures • Changes to specifications or methods compared to the previous

year • Validation status of the test methods

Review of documents & systemData collection and review

• Quality System– Deviations – OOS – Failure cause analysis

• Vendor status – Change of vendor– Supplier qualification and approval– Deviations, rejections of raw material

• Modification – Changes to the facility– Changes to machines/apparatus – Changes to super ordinate processes

Review of documents & systemData collection and review

• Quality attributes (analytical data) – Key starting material/critical material– Critical test result of IPC, intermediates– Critical quality parameters of finished product/blended – Decision on the trend- tightening of spec, CAPA, validation

requirement if any

• All quality-related returns, complaints and recalls

• Adequacy of corrective actions• Stability data

– Changes to packaging material – Process changes

Inferences from the APR

• Follow-up actions may be included but are not limited to:

Product process improvement

Analytical method improvements

In-process or final product specification review

Revalidation

Product recall or withdrawal

New packaging

Check List for APQR• Are there any outstanding validation commitments or corrective and

preventive action plans from last APQR ?• Are the processes in a validated state or is additional validation work

needed ?• Is the qualification status (IQ/OQ/PQ) acceptable ?• Are all critical aspects performing satisfactorily or are corrective/

preventive action plans required ?• Are there any significant findings concerning data trending of the

manufacturing process, starting materials, or packaging materials ?• Are all change controls implemented, and closed? Communicated to the

relevant customers and regulatory agencies?• Are all change controls, deviations, OOS investigation, complaints are

reviewed, investigated, CAPA implemented, and closed?

Check List for APQR

• Are there any significant findings concerning – changes performed ?– specifications or test methods ?– deviations and non- conformances ?

– out of specification results ?

– rejected batches, quality-related returns, customer complaints, or recalls ?

– the stability monitoring program ?

– retain sample examination ?

• Are all post- marketing commitments to Authorities met ?

• Are all required Technical Agreements in place and up-to-date ?

Thank You