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Saturday, October 20, 2012

Quality Audit -A Review


Medicinal product have to be of high quality as people lives depend on it, although end product testing of samples from each batch is important, it is not enough to ensure quality, which must be built in to the manufacturing process.
To ensure the quality, all pharmaceutical manufacturers are required to establish and implement an effective pharmaceutical QA system. To access the effectiveness of this system and to ensure it follows GMP, self-inspection and other regulatory audits must be performed.

2. Definitions:

Quality audit:
a systemic and independent examination to determine whether these arrangements are implemented effectively and are suitable to achieve these stated objectives.                                                                

Auditee:an organisation, facility or person being audited.

a person who has the appropriate qualifications and performs audit.

Pharmaceutical manufacturers commonly use audit as an effective mechanism to verify compliance with GMPs. GMP audits are designated with two important goals in mind:

          i)  Audits are intended to verify manufacturing control systems are operating under the state of control.
          ii) Audit can detect the potential problem to permit timely correction.

3. Self-inspection and Quality Audits.

·        Principle.

          The purpose of self-inspection is to evaluate the manufacturer’s compliance with GMP in all aspects of production and quality control.
          The self-inspection programme should be designed to detect any shortcomings in the implementation of GMP and to recommend the necessary corrective actions.
          The team responsible for self-inspection should consist of personnel who can evaluate the implementation of GMP objectively.
          All recommendations for corrective action should be implemented. The procedure for self-inspection should be documented, and there should be an effective follow-up programme.

·        Items for self-inspection:

Written instructions for self-inspection should be established to provide a minimum and uniform standard of requirements. These may include:

(a) Personnel;
(b) Premises including personnel facilities;
(c) maintenance of buildings and equipment;
(d) storage of starting materials and finished products;
(e) equipment;
(f) production and in-process controls;
(g) quality control;
(h) documentation;
(i) sanitation and hygiene;
(j) validation and revalidation programmes;
(k) calibration of instruments or measurement systems;
(l) recall procedures;
(m) complaints management;
(n) labels control;
(o) results of previous self-inspections and any corrective steps taken.

4. Quality audit objectives:

1.     To determine to what extent your quality system :
-         Achieves its objective.
-         Conforms to your requirements.
-         Complies with regulatory requirements.
-         Meets customers’ contractual requirements.
-         Conforms to recognized quality objectives.
2.     To improve the efficacy and effectiveness of your quality management system
3.     To verify that your quality system continues to meet requirements.

5. Role of GMP Audits:

A GMP audit programme verify whether or not QC duties and responsibilities are been carried out in accordance with specification SOPs, and GMPs.

i.                   assuring GMP compliance:

The FDA conducts routine inspections of all pharmaceutical manufacturers to determine if manufacturing and control procedures conforms to GMPs.FDA investigator make unannounced visits to the manufacturing facilities to examine facilities, equipments, personnel and records.They use systemic analysis approach where selected processes are evaluated for GMP compliance.

They may cover the following issues for this purposes:
-         Review the design, construction and maintenance facilities
-         Equipment facilities
-         Batch production records
-         Lab testing procedures
-         Stability testing records
-         Packaging and labelling control
-         Complaint records

Some firms have patterned their audit programme to be similar in content and style of FDA inspection.
The FDA investigator may select content aspect for auditing and determining the degree of compliance with GMPs. if audited system is found to be in compliance with GMP the FDA personnel will conclude that non-audited system are also in compliance with GMP.

ii. Effecting programme improvement:
Audit provides an effective mechanism for improving overall quality of QC and QA programmes.Such improvements may include the following:
-         Changing the SOPs more properly.
-         Modify manufacturing equipment or procedure.
-         Upgrading equipment or procedure
-         Improving employee training programme.
-         Developing a new or revised documentary system.
ii.                 Detecting potential problems:

GMP audit find objectionable condition that are unknown to responsible production, QC or management personnel.The auditor will see whether such actions are frequent or not.

Improper employee action may result from:
-         SOPs not containing clear instructions.
-         Inadequate employee training.
-         Lack of adequate supervision.

iv . Increasing management awareness:

For any given audits there are two outcomes, either problems are found or not.
If the problem are found, management takes an appropriate step eliminate the problem.An audit is not finding any objectionable conditions. There are two reasons for that:
§  Either there were no problem to be found
§  Auditor failed to detect objectionable condition that were actually present.

Here following are the factors to be considered:
Ø Objective of the audit
Ø Did audit reports show the specific report to management for negative findings
Ø Scope of the audit.
Ø Breadth and depth of the audit.
Ø Experience and training levels of auditors.

6. Types of Quality Audit:

I.       Internal audit.
          i) Tier one audits.
          ii) Tier two audits.
          iii) Tier three audits.
II.      External audit.
III.     Regulatory audit.

I.                  Internal audit:

Carried out by an organisation on its own system, procedures and facilities.
European legislation requires that pharmaceutical manufacturers should conduct the repeated self-inspection as a part of QA system to monitor the implementation of GMP and to propose any corrective action.Aside from legal requirements, internal audits are required for business prospective.Procedures and program of internal audit should be available and may be requested during regulatory audits.
One possible system for internal audit is three tier approach:
          i)       Tier one audits:
          ii)      Tier two audits:
          iii)     Tier three audits
i)                   Tier one audits:

-         carried out by staff of a section or department themselves.
-         audit will typically be short and focusing on housekeeping and documentation.
-         For this auditors are usually selected on the basis of knowledge and experience of area to be audited, though they should also receive some basic training.

ii)                Tier two audits:

-         typically led by local QA group comprising staff independent of the department under audit.
-         such audit will typically be longer but less frequent and are likely to focus more on system than housekeeping.
-         More exclusive training will be required for tier two auditors, with more detail on quality system and technique.

iii)              Tier three audits:

-         carried out by corporate compliance group. Alternatively external consultants can be used.
-         Such audits are often carried out to assess readiness for regulatory audit but may also be used to have an expert view on specific critical activity.
-         Tier three auditors are likely to be highly trained and experienced or specialist with an expert knowledge of GMP and other regulatory requirements for pharmaceuticals.

II.               External audit:

-         Carried out by company on its vendors or sub-contractors.
-         There is no legal requirement to conduct such audits.Need for such audit is implicit since manufacturer required to have thorough knowledge of their suppliers. Furthermore if work is contracted out they must ensure that contractors are competent to complete it in accordance with GMP.
-         External auditors typically have broad practical experience of GMP and receive quality system training equivalent to that of lead auditors. Audit system may also include specific training experts.

III.           Regulatory audit:

-         These audits are carried out by regulatory bodies against relevant system for manufacture and supply of pharmaceutical products.National regulatory bodies such as medicine control agency (MCA) in the UK, and FDA in USA are statutory bodies responsible for carrying out such audits. These audits may be unannounced (eg. MCA currently performs about 10% of their audits like this in UK) as manufacturers are expected to be complying with GMP at all times.Regulatory bodies from other countries in which the products are sold may also audit companies. Eg. FDA audits European manufacturers.
-         Regulatory inspectors are extensively trained and they are knowledgeable. All MCA inspectors are relatively qualified and have minimum of 5 years’ experience in the manufacturing operations.Failure to pass regulatory audits can receive restriction on a manufacturing or import/export license. Therefore it is vital that companies have define process for handling audit and that staff.
-         Currently different regulatory bodies have distinct audit stages and requirements but to reduce cost and audit burden on manufacturer, they have been moved towards sharing and mutually recognising audits.
There has been a pharmaceutical inspection convention (PIC) since 1971 based in Geneva. Under PIC, the health authorities of countries agree that if manufacturer’s consent information obtained during information may be exchanged. PIC holds regular meeting for representative of member countries to discuss common strategy.

7. Inspection Processes:

Inspection procedures may vary in nature according to  the objectives:

i.                   Routine inspection.
ii.                 Concise inspection.
iii.              Follow-up inspection.
iv.              Special inspection.
v.                 Quality system review.
vi.              Periodic evaluation.

i.                   Routine inspection:

There is a full inspection of all applicable components of GMP and licensing provisions:
-         It may be indicated when the manufacturer:
-         Is newly established.
-         Request renewal of license to operate.
-         Has introduced new product lines or new products or has made significant modification to methods or processes, equipments etc.
-         Has a history of non-compliance with GMP.
-         Has not been inspected during the last 3-5years.

ii.Concise inspection:

Manufacturers with a consistent record of compliance with GMP through previous routine inspection are eligible for it.The focus of this is on limited no. of GMP requirements selected as indicator of overall performance. It also focuses on any significant change that could have been introduced since the last inspection. Collectively the information will indicate overall attitude of the firm towards GMP.Evidences of unsatisfactory GMP performance during this inspection should trigger a more comprehensive inspection.

iii. Follow-up inspection:

Follow-up inspections are made to monitor the results of corrective actions. They are normally carried out from 6 weeks to 6 months after the initial inspection, depending upon the nature of defects and work to be undertaken. They are limited to specific GMP requirements that have been observed or that have been inadequately implemented.

iv. Special inspection:

Special visit may be necessary to undertake spot checks following complaints or recalls related to suspected quality defects in products.Such inspection may be focused on one product, a group of related products of specific operations such as mixing, sterilisation or labelling.
Further reason for special visit is to gather specific information in specific operation and to advise the manufacture of regulatory requirements.

v. Quality system review:

Its purpose is to describe a quality assurance system that has been shown to operate satisfactorily it should also be defined management structure needed to implement the policy along with the procedure needed to ensure that adequate quality standards are set for the product.It also checks whether manufacturing processes are correctly defined records are kept and quality control and other QA active these are carried out.

vi. Periodic evaluation:

Periodic evaluations are routine review and assessment of quality standards.
It is done to check the need for changes in drug product manufacturing and control procedures.
Employees those are directly responsible for a system under review normally perform periodic evaluation.

8. Guidelines For Planning, Managing, And Performing Quality Audits

1.     When To Do An Audit.
2.    Auditee’s Job.
3.     Develop Of Audit Management Process.
4.     Prepare An Audit Plan.
5.     Perform The Quality Audit.
6.     Prepare The Audit Report.
7.     Submit The Audit Report.
8.     Follow-up Steps.

1.                 When to do an audit:

An auditee may carry out audits on a regular basis to improve quality system performance or to achieve business objectives.
A client may initiate an audit because:
-         A regulatory agency requires an audit.
-         A previous audit indicated that a follow-up audit was necessary.
-         An auditee has made important changes in:
-         Policies or procedures.
-         Technologies or techniques.
-         Management or organisation.

2.                 Auditee’s job:

-         Explain the nature, purpose, and scope of the audit to employees.
-         Appoint employees to accompany and assist the auditors.
-         Ensure that all personnel co-oparate fully with the audit team.
-         Provide the resources the audit team need to do the audit.
-         Allow auditors to examine all documents, records, and facilities.
-         Correct and prevent problems that were identified by the audit.

3.                 Develop of audit management process:

Develop of audit management process that is formally separate and entirely independent of the quality system to be audited.

i. Audit team:
          comprise of audit manager under which lead auditor and auditor works.

ii. Select audit manager:
Audit manager must:
-         Have practical quality system audit experience.
-         Identify the quality standards that will be used to perform the quality system audit.
-         Ensure that audit team will be competent and capable of performing quality audits.
-         Select auditors and lead auditors. However, a separate auditor evaluation panel should approve the audit manager’s selection.
iii.              Audit manger’s job:

a.     Manage the audit process:

Audit manager should manage the audit process. The audit manager should:
-         Ensure that all auditors and lead auditors are knowledgeable and suitably trained.
-         Develop and enforce a code of ethics to govern the audit process.
-         Monitor and evaluate the performance of their audit team in order to improve their efficiency and effectiveness.
-         Ensure that all auditors make the same observations and draw the same conclusions when all having the same evidences. Audit manager should help guarantee consistency.

b.    Support the audit process:

Audit manager should support the audit process.
The audit manager should:
-         Plan and schedule the audit activities.
-         Perform the audit reporting process.
-         Control the audit follow-up process.
-         Protect the confidentiality of the audit information.
-         Ensure that auditors have the resources they need.

c. Support continuous improvement:

Audit manager should support and encourage both the auditor and other personnel to continuously improve the audit process.

iv. Select lead auditor:
Audit manager should select a lead auditor who has the appropriate knowledge and skill, and who also knows how to:
-         Manage and motivate the audit team.
-         Exploit the talent and expertise of team members.

v. The lead auditors job:

-         Assign audit task.
-         Help select auditors.
-         Orient the audit team.
-         Prepare the audit plan.
-         Define the auditors’ qualifications.
-         Clarify quality audit requirements.
-         Communicate audit requirements.
-         Prepare audit forms and checklists.
-         Review quality system documents.
-         Report major nonconformities immediately.
-         Interact with auditee’s management and staff.
-         Prepare, submit, and discuss audit reports.

vii.            Select auditors:

Audit manager should select auditors who:
-         Understand the standards that will be applied during the audit.
-         Are familiar with the auditee’s products, services, and activities.
-         Have studied the regulations that govern the auditee’s activities.
-         Have the technical qualifications needed to carry out an audit.
-         Have the professional qualifications needed to carry out an audit.
-         auditor must behave in a professional manner.

Auditor must:
-         Have integrity and be independent and objective.
-         Have the authority they need to do a proper job.
-         Avoid compromising the audit by discussing audit details with auditee during audit.

viii.         Auditor’s job:

-         Evaluate the quality system.
-         Carry out assigned audit task.
-         Comply with audit requirements.
-         Respect all confidentiality requirements.
-         Collect evidence about the quality system.
-         Document audit observations and conclusions.
-         Safeguard audit documents, records, and reports.
-         Determine whether quality policy is being applied.
-         Find out if the quality objectives are being achieved.
-         See whether quality procedures are being followed.
-         Detect evidences that might invalidate audit results.

4. Prepare an audit plan:
The auditors should begin planning the audit by reviewing documents(eg.manuals, SOPs) that both describe the quality management system and explain how it is attempting to meet quality requirements.If this preliminary reviewing that the quality management system is inadequate, the audit process should be suspended until this inadequacy is resolved.The plan should be prepared by the lead auditor and approved by client before the audit begins.

Ø The audit plan should:
-         Define the audit objectives and scope of the audit.
-         Explain how long each phase of the audit will take.
-         Specify where and when the audit will be carried out.
-         Introduce the lead auditor and his team members.
-         Identify the quality elements that will be audited.
-         Identify the groups and areas that will be audited.
-         List the documents and records that will be studied.
-         List the people who are responsible for quality and whose areas and functions will be audited.
-         Explain when meetings will be held with auditee’s senior management.
-         Clarify who will get the final audit report when it will be ready .

4.                 Perform The Quality Audit:
Start the quality audit: start the audit by having an opening meeting with the auditors’ senior management this meeting should:
-         Introduce the audit team.
-         Clarify the scope, objectives, and schedule.
-         Explain how the audit will be carried out.
-         Confirm that the auditee is ready to support the audit process.

i. Prepare audit working papers:
-         Prepare the checklist (use to evaluate quality management system elements).
-         Prepare forms (use to record observations and collect evidences).
ii. Quality audit done by:
-         Interviewing personnel.
-         Reading documents.
-         Reviewing manuals.
-         Studying records.
-         Reading reports.
-         Scanning files.
-         Analysing data.
-         Observing activities.
-         Examining conditions.
iii. Confirm interview evidences:
Evidences collected through interviews should, where ever possible, be confirmed by more objective means.
iv. Investigate clues:
Clues that point out the possible quality management system non conformities should be thoroughly and completely investigated.
vi. Document observation:
auditor must study the evidences and document their observations and make a list of key nonconformities. They must ensure  that non conformities are:
Supported by evidence.
Cross-referenced to the standards those are being violated.
vii. Draw conclusions:
          auditors must draw the conclusions about how well the quality system is applying its policies and achieving its objectives.
viii. Discuss the results:
          auditors should discuss evidences, observations, conclusions, recommendations, and non-conformities with auditee senior managers before they prepare the final audit report.

6. Prepare The Audit Report:
The audit report should be dated and signed by the lead auditor. This report should include:
-         A detailed audit plan.
-         Review of the evidence that was collected.
-         A discussion of the conclusion that were drawn.
-         A list of the nonconformities that were identified.
-         A judgement about how well the quality system complies with all quality system requirements.
-         An assessment of the quality system’s ability to achieve quality objectives and apply the quality system policy.

7. Submit the audit report:The lead auditor should send the audit report to the client and the client should send it to the auditee.
8. Follow-up Steps:
a)     Take remedial action: the auditee should expected to take whatever actions are necessary to correct or prevent nonconformities.
b)    Schedule follow-up audit:Follow-up audits should be scheduled in order to verify that corrective and preventive actions were taken.


2.     “Pharmaceutical auditing”  ( Pharmaceutical quality group monograph No.5: IQA, 2001, ISBN 090681068X)
3.     “Systemic audit of parenteral drug GMPs” by Ronald F. Tetzlaff (From- pharmaceutical dosage form –parenteral medication vol.-3 By Kenneth E Evis, Herbet A Liberman, Leon Lachman)



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