Ich q7 implementation

Easy Interpretations & Implementation of

important sections of Q7 Presentation- 01 Dr. Nandkumar Chodankar

ASolu&on Pharmaceu&cal Pvt. Ltd. Mumbai India

[email protected]

Dr. Nandkumar Chodankar- Asolution Pharmaceutical Pvt. Ltd

All 19 Chapters in the ICH Q7 Guidelines are Important and must be followed systematically in order to

achieve GMP This is the first presentation on ICH Q7 Interpretation &

Implementation

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1. INTRODUCTION 2. QUALITY MANAGEMENT 3. PERSONNEL 4. BUILDINGS AND FACILITIES 5. PROCESS EQUIPMENT 6. DOCUMENTATION AND RECORDS 7. MATERIALS MANAGEMENT 8. PRODUCTION AND IN-PROCESS CONTROLS 9. PACKAGING AND IDENTIFICATION LABELLING OF APIS

AND INTERMEDIATES 10. STORAGE AND DISTRIBUTION 11. LABORATORY CONTROLS

ICH Q 7

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12. VALIDATION 13. CHANGE CONTROL 14. REJECTION AND RE-USE OF MATERIALS 15. COMPLAINTS AND RECALLS 16. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES) 17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS,

AND RELABELLERS 18. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL

CULTURE/FERMENTATION 19. APIS FOR USE IN CLINICAL TRIALS The ICH Q7 Guide covers APIs that are manufactured by chemical

synthesis, extraction, cell culture/fermentation, by recovery from natural sources, or by any combination of these processes. Specific guidance for APIs manufactured by cell culture/fermentation is described in Section 18.

ICH Q 7

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• Implementation of cGMP ensures systems for – proper design, – monitoring, and – control of manufacturing

processes and facilities.

Quality Assurance

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Pharma companies must be Pa6ent Centered rather than just Business Centered

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1.1 Objec&ve of ICH Q7-‐ What vs. How?

2. Quality Management -‐ Sr. Management Responsibility

2.4 Internal Audit – Efficient for Gaps iden&fica&on & con&nuous improvement

2.5 Product Quality Review

3 Personnel

4 Building & Facili6es

SYNOPSIS of this Presenta&on

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ICH Q7 Implementation “What to do” Vs. “How to do”?

ICH Q 7 Objectives 1. Quality Management System - GMP for

APIs (Drug Substances) 2. To ensure that APIs meet the requirements

for quality and purity that they purport or are represented to possess.

ISPE Baseline Guides, ICH & APIC Guidelines

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ICH Q7- ISPE Concepts

Cri&cal Intermediate

Isola&on of Pure Product

Physical Processing & Packaging

Supply Chain

Star6ng Step for API Manufacturing

Non-‐cri&cal

Pre-‐cri&cal

Sound scientific judgment should prevail when implementing a Quality Management System to incorporate GMP

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ICH Q7& Regulatory Requirements • Q7 Guide covers only GMP relevant steps for

Inspection compliance • Regulatory Agencies/ authorities may ask for

more information • Companies are responsible for proposing API

Starting Materials • The technical, quality & regulatory groups

should agree on the proposed starting materials based on current regulatory requirement

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Quality Management - HOW? Sr. Management

Repor6ng System Resources

Mul6ple Responsibili6es Quality Related MaQers

Quality Unit

Con&nuous Improvement

Manufacturing

Regular report system should be made available to senior management by the QU informing of acute occurrences of quality related complaints, cri6cal devia6ons, recalls, etc.

Senior management should review & agree any recommenda6ons & ensure that appropriate resources are made available.

Quality (or key) performance indicators could be installed to evaluate con6nuous quality improvement of each department.

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“No body told me”

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ICH Q7- Quality Management 2.15: Logging- All activities should be

directly recorded at the time they are performed in legible documents like retrievable and traceable note-books, electronic records (validated system), etc.

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Root cause inves6ga6on becomes difficult because of missing entries -‐“observa6on”

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Responsibilities of the Quality Unit (s) Delegation of Responsibilities by QU

2.20 The quality unit(s) should be involved in all quality-related matters 2.21 The QUs should review and approve all appropriate quality-related documents. 2.22 The main responsibilities of the independent QUs should not be delegated. These responsibilities should be described in writing and should include but not necessarily be limited to: Releasing or rejecting all

APIs. 1. Releasing or rejecting intermediates for use outside the control of the manufacturing company; 2. Establishing a system to release or reject raw materials, intermediates, packaging and labeling materials; 3. Reviewing completed batch production and laboratory control records of critical process steps before release of the API for

distribution; 4. Making sure that critical deviations are investigated and resolved; 5. Approving all specifications and master production instructions; 6. Approving all procedures impacting the quality of intermediates or APIs; 7. Making sure that internal audits (self-inspections) are performed Approving intermediate and API contract manufacturers; 9. Approving changes that potentially impact intermediate or API quality; 10. Reviewing and approving validation protocols and reports; 11. Making sure that quality related complaints are investigated and resolved; 12. Making sure that effective systems are used for maintaining and calibrating critical equipment; 13. Making sure that materials are appropriately tested and the results are reported; 14. Making sure that there is stability data to support retest or expiry dates and storage conditions on APIs and/or intermediates

where appropriate; and 15. Performing product quality reviews (as defined in Section 2.5).

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• Responsibilities may be delegated to other department- provided – QU ensures that Systems are in place with

adequate control / supervision – Levels of control as per the nature of the activity – "make sure” - QU assigns responsibilities &

ensures by audit that systems are in place – "be involved” – ownership - QU gets personally

involvement – "establishing”- QU issues a system or

procedure on its assigned duties

Responsibilities of the Quality Unit (s) 2.22 Delegation of Responsibilities by QU

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2.22: “should not be delegated” vs “must not be delegated”

• QU “must” review of all Critical steps in Batch Production record (all unit operations) including laboratory records

• Review of all other steps (non critical) may be delegated (ICH Q7, section 6.71)

• System for defining what changes are likely to “impact intermediate or API quality” (ICH Q7,section 6.71)

• All changes have to be evaluated & communicated

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Responsibilities of the Quality Unit (s) 2.22: 14-Stability data for intermediates

• At least “Limited stability data for Intermediates to be sold”. (for reference see ICH Q7 chapter 11.60). Full stability program need not be applied

• In many instances, “a retest of the material prior to use or shipment” may be sufficient with justification

• Data may be generated during the development phase or during validation to support storage periods during campaign production or storage of left–over between two campaigns.

• If production has been delegated the responsibility of release of Intermediates for filed specifications, QU should perform periodical review

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• The responsibility for production activities should be described in writing, and should include but not necessarily be limited to: 1. Preparing, reviewing, approving and distributing the instructions for the

production of intermediates or APIs according to written procedures; 2. Producing APIs and, when appropriate, intermediates according to pre-

approved instructions; 3. Reviewing all production batch records and ensuring that these are

completed and signed; 4. Making sure that all production deviations are reported and evaluated and

that critical deviations are investigated and the conclusions are recorded; 5. Making sure that production facilities are clean and when appropriate

disinfected; 6. Making sure that the necessary calibrations are performed and records kept; 7. Making sure that the premises and equipment are maintained and records

kept; 8. Making sure that validation protocols and reports are reviewed and

approved; 9. Evaluating proposed changes in product, process or equipment; and 10. Making sure that new and, when appropriate, modified facilities and

equipment are qualified.

2.3 Responsibility for Production Activities

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2.40 In order to verify compliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule

2.41 Audit findings and corrective actions should be documented and brought to the attention of responsible management of the firm. Agreed corrective actions should be completed in a timely and effective manner

2.4 Internal Audits (Self Inspection)

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Internal Audit –Efficiency • A valuable management tool to evaluate

– whether the company is in compliance with the principles of GMP and

– What are the additional requirements (resources) of the company which are integrated in the QMS.

• The evaluation should be made by – trained auditors, experienced in auditing skills and

recruited from various departments of the company, if possible

• Quality Inspection Team (QIT) of normally 2 persons is recommended, however additional experts (e.g. engineers, micro-biologists, etc.) could increase audit efficiency

• QU should always be represented in the team (but not as leader or policeman)

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• The QU should be responsible for coordinating activities: – pre-audit meetings for the QIT (brain storming) – identifying major areas of concern and preparation of

questionnaire – collecting historical information such as deviations, changes,

complaints, reprocessing, previous internal audit reports – issuing the agenda and distribution to the Auditee in due time – coordinating the activities of the QIT – starting the (internal) audit and summarizing the findings in a

close out meeting – issuing the audit report, on the basis of the close out meeting – proposing corrective measures or improvements to management – proposing a Schedule for re-audit in case of major findings – follow-up

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Internal Audit –Efficiency

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• Other members of the QIT - to be involved in asking and taking extensive meaningful notes

• Auditing process should be clearly defined & standard documents should be available like: – Definition of auditing process, system or product – Covering Letter – Report Form – Audit Team Evaluation Form – Follow-up Report – Training Program

• The frequency – – based on risk (a formal risk assessment may not be

necessary) – the compliance status of the area to be audited. – It may vary from half a yearly to three yearly (with logical

rationale behind the frequency) 20

Internal Audit –Efficiency

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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.

2.51 The results of this review should be evaluated and an assessment made of whether corrective action 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.

2.5 Product Quality Review

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2.5 Product Quality Review Annual Vs Campaign concept

• Major objective of Product Quality Review 1. To evaluate the compliance status of the manufacturing

(process, packaging, labeling, tests, etc.) & 2. To identify areas of improvement based on the

evaluation of key data. (OOT, DRIFT - Root Cause) • QU must involve other departments, like-

• Production, • Engineering, • Maintenance, • Purchase, etc.

• QU is held responsible for the release and approval of the final report

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2.5 Product Quality Review • For meaningful review identify

– The critical “in-process controls” and – Critical “API or relevant intermediate’s Test Results” – Normally critical API test results may be used to

indicate “the consistency of the process” or to “assess potential deviations in the quality” of the API itself (OOT, DRIFT- Use of Statistical tool)

– Failure frequency to meet such limits – The critical reaction parameters & Time cycle

• Ideally the critical parameters are identified in the development report prepared prior to process validation but may also be based on experience for well established processes

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2.5 Product Quality Review (PQR) “Process Drift”

• Where the data indicates that there is a “drift in process capability”, actions should be taken to evaluate the causes and improve performance preferably in the forthcoming review period of next campaign

• Use of “Statistical tools” to establish key performance indicators is good approach for “Continuous Improvement”

Ref. Nandkumar Chodankar 1. FDA & PQRA Workshop at Washington – December 1-3, 2010 2. Chapter on Process drift – Achieving Quality & Compliance Excellency in

Pharmaceuticals- Master GMP Guideline- edited by Madhu Raje Saghee

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2.5 Product Quality Review • 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 & improve performance

• Common causes for batch failures & recurring deviations – Equipment not functioning correctly or in need of

maintenance or replacement. Out of Calibration of critical instruments

– Inadequate batch instructions or training of operators – Tightly defined Process parameters that the equipment is

not capable of routinely achieving the acceptance criteria – Non-homogeneous product or inadequate sampling

procedures – Poor quality RMs or lack of control of RM suppliers – In-process controls

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2.5 Product Quality Review • The impact of changes (see chapter

“Change Control”) introduced to the processes or analytical methods should also be carefully evaluated to look for any direct effect on the critical test results and the process validation status

• The impact of cumulative changes, should be considered when reviewing the impact of changes during PQRs

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2.5 Product Quality Review • Trends in the stability monitoring program should

be reviewed against changes introduced to the processes or analytical methods

• Any trends indicating deterioration of product which could affect the retest period or expiry date of the API should be identified and an investigation into the causes should be performed

• The status of quality related returns, complaints or recalls should evaluate the adequacy of corrective actions and any trends which require further investigation

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2.5 Product Quality Review • Based on the Product Quality Review a list of clearly

defined corrective actions & recommendations should form the basis of the objectives for the product in the next campaign. This should include the possibility of process revalidation where significant changes or alterations in the trends of the key quality data is indicated

• Senior management should be involved in reviewing the recommendations & in providing the necessary resources & priorities to ensure the corrective actions & recommendations are implemented

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OOT DRIFT

List of Correc&ve Ac&ons

Recommenda&on Process

Revalida&on

Forth coming Campaign

Con&nuous Improvement

Management Feed back

Change Control

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PQR

Net Working

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Chapter 3 Personnel General Remarks

• The environment must encourage and recognize excellence. Staff must understand how they can influence quality, GMP compliance and contribute to improvement

• Staff at all levels must be competent and be effectively managed

• It is stated in section 3.11 that the responsibilities of all personnel engaged in the manufacture of intermediates and APIs should be specified in writing

• This can be accomplished either in a generic way for a group of personnel e.g., ware-house personnel or operators in chemical production

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3.1 Personnel Qualifications 3.10 There should be an adequate number of personnel qualified by appropriate education, training and/or

experience to perform and supervise the manufacture of intermediates and APIs. 3.11 The responsibilities of all personnel engaged in the manufacture of intermediates and APIs should be

specified in writing. 3.12 Training should be regularly conducted by qualified individuals and should cover, at a minimum, the particular

operations that the employee performs and GMP as it relates to the employee's functions. Records of training should be maintained. Training should be periodically assessed. 3.20 Personnel should practice good sanitation and health habits.

3.1 Personnel Hygiene 3.21 Personnel should wear clean clothing suitable for the manufacturing activity with which they are involved and

this clothing should be changed when appropriate. Additional protective apparel, such as head, face, hand, and arm coverings, should be worn when necessary, to protect intermediates and APIs from contamination.

3.22 Personnel should avoid direct contact with intermediates or APIs. 3.23 Smoking, eating, drinking, chewing and the storage of food should be restricted to certain designated areas

separate from the manufacturing areas. 3.24 Personnel suffering from an infectious disease or having open lesions on the exposed surface of the body

should not engage in activities that could result in compromising the quality of APIs. Any person shown at any time (either by medical examination or supervisory observation) to have an apparent illness or open lesions should be excluded from activities where the health condition could adversely affect the quality of the APIs until the condition is corrected or qualified medical personnel determine that the person's inclusion would not jeopardize the safety or quality of the APIs.

3.3 Consultants 3.30 Consultants advising on the manufacture and control of intermediates or APIs should have sufficient

education, training, and experience, or any combination thereof, to advise on the subject for which they are retained.

3.31 Records should be maintained stating the name, address, qualifications, and type of service provided by these consultants.

3 Personnel

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Chapter 3 Personnel - Responsibilities

• For persons having a more specific responsibility, e.g., supervisors, process engineers, it might be appropriate to stipulate individual responsibilities as per their role and functions

• A possible way of indicating this is to use a matrix in which the responsibilities are defined. Another way of doing it could be the use of separate columns in a process flow chart indicating which unit or function (person) is responsible for what action

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Chapter 3 Personnel • Mixture of any of these can be used so long

as the quality critical responsibilities defined in Section 2 are suitably documented

• Job descriptions or function descriptions should identify the main purpose, role dimensions, outputs/responsibilities, reporting details and required competencies. These should be reviewed regularly

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Chapter 4 Buildings and Facilities 4.1 Design and Construction

• It is important to realize that API manufacturing plants are designed and constructed in various different ways depending on the chemistry, the nature of the API, the location of the plant (country, climatic region), GMP philosophy of the individual company etc.

• Existing (old) plants and “state of the art designed” (new) plants are expected to be very different in design and construction

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Ware House U6lity

Physical Processing

& Packaging

Isola6

on of A

PI

Pure Produ

ct

Cri6cal

Interm

ediate

Non-‐cri6cal Use of S M

GMP

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GMP

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Short cuts that lead to problem 14. Reprocessing, Reworking, Recovery 5.3 Calibration 12.7 Cleaning 6. Documentation –Logging the operation • Casual Workers • Changing the source of supplier • During winter- putting off AC’s or keeping the doors open • Specific Training • Instrument qualification • Re-sampling • On line HPLC (time consuming Tests) • Too many restrictions like un-necessary entry barriers. • Water quality Sophisticated purification systems • Maintenance – Quick-fit solution • Root cause analysis • Primary reference standards – impurities, structure elucidation • Impurity Profile • COA 11.44

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Nandkumar Chodankar [email protected]

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This is just the beginning To be Con6nued

THANK YOU

August 1st 2013

Ich q7 implementation

Business

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