QMS Flashcards
What can you tell me about data integrity?
Data integrity in relation to medicinal products has been defined as;
‘The extent to which all data are complete, consistent and accurate throughout the data lifecycle’
‘The completeness, consistency, and accuracy of data’
‘The degree to which data are complete, consistent, accurate, trustworthy and reliable and that these characteristics of the data are maintained throughout the data life cycle’
Key principle of data integrity is ‘ALCOA’, i.e. that data should be:
o A - Attributable to the person generating the data
o L - Legible and permanent
o C - Contemporaneous
o O - Original record (or ‘true copy’)
o A - Accurate
The requirement for complete and accurate records has long been incorporated as part of GLP, GMP, GDP and GCP regulations and guidelines.
Current Guidance
a) US FDA 21 CFR Part 11- Electronic Records
b) EudraLex Volume 4 Annex 11- Computerised Systems.
c) MHRA GMP Data Integrity Definitions and Guidance for Industry- March 2015. <require compliance of systems by 01Jan18>
Describe key elements of a pharmaceutical quality system
ICH Q10 model: Four key elements to promote the lifecycle approach to product quality, are:
* Process performance and product quality monitoring system;
* Corrective action and preventive action (CAPA) system;
* Change management system;
* Management review of process performance and product quality.
These elements should be applied in a manner that is appropriate and proportionate to each of the product lifecycle stages.
Discuss validation requirements (from the perspective of process, analytical method qualification and equipment) in clinical trials versus marketed products.
<EU GMP Volume 4 Annex 13>
- Production processes for IMPs are not expected to be validated to the extent necessary for routine production - Premises and equipment are expected to be qualified.
- For sterile products, the validation of sterilising processes should be of the same standard as for products authorised for marketing.
- When required, virus inactivation/removal and that of other impurities of biological origin should be demonstrated
ICH Q10: “The elements of ICH Q10 should be applied in a manner that is appropriate and proportionate to each of the product lifecycle stages, recognising the differences among, and the different goals of each stage.” For development, emphasis is on establishing a control strategy.
What would you see in a batch manufacturing record?
EU GMP Volume 4 Chapter 4: Documentation <+ can use your own batch record as an example>
a) Name and batch number of the product,
b) Dates and times of commencement, of significant intermediate stages and of completion of production;
c) Identification (initials) of the operator(s) who performed each significant step of the process and, where appropriate, the name of any person who checked these operations;
d) The batch number and/or analytical control number as well as the quantities of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added);
e) Any relevant processing operation or event and major equipment used;
f) A record of the in-process controls and the initials of the person(s) carrying them out, and the results obtained;
g) The product yield obtained at different and pertinent stages of manufacture;
h) Notes on special problems including details, with signed authorisation for any deviation from the Manufacturing Formula and Processing Instructions;
i) Approval by the person responsible for the processing operations.
What would you see in a batch packaging record?
EU GMP Volume 4 Chapter 4: Documentation
a) Name and batch number of the product,
b) The date(s) and times of the packaging operations;
c) Identification (initials) of the operator(s) who performed each significant step of the process and, where appropriate, the name of any person who checked these operations;
d) Records of checks for identity and conformity with the packaging instructions, including the results of in-process controls;
e) Details of the packaging operations carried out, including references to equipment and the packaging lines used;
f) Whenever possible, samples of printed packaging materials used, including specimens of the batch coding, expiry dating and any additional overprinting;
g) Notes on any special problems or unusual events including details, with signed authorisation for any deviation from the Packaging Instructions;
h) The quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of obtained product, in order to provide for an adequate reconciliation. Where there are there are robust electronic controls in place during packaging there may be justification for not including this information
i) Approval by the person responsible for the packaging operations
QMS, what is the structure, how do you know if it is performing?
ICH Q10/ Eudralex volume 4 part 1 chapter 1: PQS
A Quality Manual or equivalent documentation approach should be established and should contain the description of the PQS. The description should include:
(a) The quality policy (see section III (2)).
(b) The scope of the pharmaceutical quality system.
(c) Identification of the pharmaceutical quality system processes, as well as their sequences, linkages, and interdependencies. Process maps and flow charts can be useful tools to facilitate depicting PQS processes in a visual manner.
(d) Management responsibilities within the pharmaceutical quality system.
How you know it is performing:
- Process performance and product quality monitoring system
- Conduct management reviews of process performance and product quality and of the PQS
- Performance indicators that measure progress against quality objectives should be established, monitored, communicated regularly, and acted upon as appropriate as described.
- Management should have a formal process for reviewing the PQS on a periodic basis. The review should include:
(a) Measurement of achievement of pharmaceutical quality system objectives
(b) Assessment of performance indicators used to monitor the effectiveness of processes, such as:
(1) Complaint, deviation, CAPA and change management processes
(2) Feedback on outsourced activities
(3) Self-assessment processes including risk assessments, trending, and audits
(4) External assessments such as regulatory inspections and findings and customer audits
Describe a recall process.
Who do you inform?
What If centrally authorised?
Eudralex Volume 4- Part 1: Chapter 8: Complaints, Quality Defects and Product Recalls
- Follow own internal procedure- led by site lead, HoQ and includes QP & SMEs.
- established written procedures, regularly reviewed and updated when
- After a product has been placed on the market, any retrieval is regarded and managed as a recall.
- Should be capable of being initiated promptly and at any time.
-Batch/product distribution records readily available to persons responsible and contain sufficient information on wholesalers& directly supplied customers -addresses, phone/fax in& out hours, batches and amounts
-For IMP all trial sites should be identified and the countries of destination indicated. If subject to MA, inform the MAH. The sponsor should implement rapid unblinding to extent necessary for a prompt recall. - Consideration given following consultation with the concerned CA, as to how far recall action should extend. CA should also be informed in situations in which no recall action is being proposed e.g. expired batch.
-All concerned CA should be informed in advance. If very serious, action may have to be taken before this.
-considered whether the proposed recall action may affect different markets in different ways (eg shortgage)
-progress of the recall process should be recorded until closure and a final report issued, inc reconciliation
-Effectiveness of arrangements for recalls should be periodically evaluated in/out office hours - other potential risk-reducing actions that may be considered in order to manage the risks presented by quality defects. May include cautionary communications to healthcare professionals on a caseby-case basis and discussed with the concerned CA.
Tell me about recall levels and timings for each class
Class 1 - immediate recall, because the product poses a serious or life threatening risk to health.
Class 2 - recall within 48 hours, because the defect could harm the patient but is not life threatening.
Class 3 - requires action to be taken within 5 days, defect is unlikely to harm patients & is being carried out for reasons other than patient safety.
Class 4 - alerts advise caution to be exercised when using the product, but indicate that the product poses no threat to patient safety
Most recalls fall into classes 2 or 3. Recall examples:
Class 1 - Wrong product (label and contents are different products), Microbial contamination of sterile injectable
Class 2 - Missing or incorrect information - leaflets or inserts, Non-compliance with specification (e.g. assay, stability, fill/weight).
Class 3 - Faulty packaging – for example, wrong or missing batch number or expiry date, Faulty closure.
Class 4 - PIL typo, rror with the barcodes
What should be included in a management review?
ICH Q10/ Eudralex vol 4 part 1: Chapter 1 PQS:
Management review should provide assurance that process performance and product quality are managed over the lifecycle. Depending on the size and complexity of the company, management review can be a series of reviews at various levels of management and should include a timely and effective communication and escalation process to raise appropriate quality issues to senior levels of management for review.
The management review system should include:
(1) The results of regulatory inspections and findings, audits and other assessments, and commitments made to regulatory authorities
(2) Periodic quality reviews, that can include:
(i) Measures of customer satisfaction such as product quality complaints and recalls
(ii) Conclusions of process performance and product quality monitoring
(iii) The effectiveness of process and product changes including those arising from corrective action and preventive actions
(3) Any follow-up actions from previous management reviews
(b) The management review system should identify appropriate actions, such as:
(1) Improvements to manufacturing processes and products
(2) Provision, training, and/or realignment of resources
Management should have a formal process for reviewing the pharmaceutical quality system on a periodic basis. The review should include:
(a) Measurement of achievement of pharmaceutical quality system objectives
(b) Assessment of performance indicators that can be used to monitor the effectiveness of processes within the PQS- ie:
(1) Complaint, deviation, CAPA and change management processes
(2) Feedback on outsourced activities
(3) Self-assessment processes including risk assessments, trending, and audits
(4) External assessments such as regulatory inspections and findings and customer audits
What are key aspects of Complaints procedure?
Eudralex vol 4 part 1 Chapter 8 - Complaints and Product Recall
- Written procedures. - All complaints documented and assessed to establish if they represent a potential quality defect or other issue.
- Special attention to establishing whether a complaint or suspected quality defect relates to falsification.
- Documented appropriately and communicated to relevant group /person for the investigation & management e.g suspected adverse events.
- Procedures to facilitate investigation of the quality of a batch to support an investigation into a reported suspected adverse event.
Include;
i. Description of the reported quality defect. ii. Determination of extent of the quality defect. The Checking or testing of reference and/or retention samples considered and in certain cases, a review of the batch production record, certification/ distribution records
iii. Need to request a sample, or the return, of the defective product and an appropriate evaluation carried out.
iv. Assessment of the risk(s) posed by the quality defect (severity and extent)
v. Decision-making process in relation to the distribution network, e.g. recalls or other actions.
vi. Assess impact any recall may have on availability of the product to patients/animals notify the relevant authorities of impact.
vii. internal & external communications viii. identification of potential root cause(s) ix. need for appropriate CAPA and effectiveness assssessment
tools and methods for risk management and their interface with regulatory requirements
ICH Q9:
Basic tools: Flowcharts, Check Sheets, Process Mapping, Cause and Effect Diagrams (also called an Ishikawa diagram or fish bone
diagram)
1.2 Failure Mode Effects Analysis (FMEA)
I.3 Failure Mode, Effects and Criticality Analysis (FMECA)
I.4 Fault Tree Analysis (FTA)
I.5 Hazard Analysis and Critical Control Points (HACCP)
I.6 Hazard Operability Analysis (HAZOP)
I.7 Preliminary Hazard Analysis (PHA)
I.8 Risk Ranking and Filtering
I.9 Supporting Statistical Tools <Control charts, for example: — Acceptance control charts (see ISO 7966) — Control charts with arithmetic average and warning limits (see ISO 7873) — Cumulative sum charts (see ISO 7871) — Shewhart control charts (see ISO 8258) — Weighted moving average
- Design of experiments (DOE) -Histograms -Pareto charts -Process capability analysis
what are the principles, applications and interpretation of stability testing (prototols + methods) during development to determine shelf life and support ongoing marketing of products?
Real time & Accelerated Stability studies
A Stability Indicating Method is defined as a validated analytical procedure that accurate and precisely measure active ingredients (drug substance or drug product) free from process impurities, excipients and degradation products.
There are basically 3 steps necessary for developing a tability Indicating Method-
Step 1: generation of degraded samples for testing selectivity of the method
Step 2: method development (manipulating and evaluating selectivity/specificity)
Step 3: Method validation
Astability indicating method can be any analytical method capable of measuring a loss of API upon storage.(i.e., it must be able to discriminate between the API and any degradants/impurities/excipients, and measure the potential loss upon degradation. In early studies, or in forced degradation studies, it could also be desired to measure the degradants).
You are about to audit an Indian Suppliers QMS, what are you looking for and what are your concerns?
After a successful audit, need to arrange receipt in the EU. What needs to be in place before this can happen?
What changes to Annex 16’s update impact on drug receipt?
Can you describe how you would use QRM in a PPM programme
Asked about what does my mock recall process look like
