20190928-Quality Assurance in Pharmaceutical Industries-Eng.Mohammad Nazzal

What is a drug? “A Chemical Substance that Interacts with a Living System and Produces a Biological Response”

Pharmaceutical dosage Forms  Tablets  Capsules  Solutions  Suspensions  Creams & Ointments  Injectable product  Sprays  Suppositories

Tablet production area

Tablet production  Weighing process

Tablet production  Granulation process

Tablet production  Mixing process

Tablet production  Compression process

Tablet production  Coating process

Tablet production  Blistering process

The Quality

The Quality  Definition: The totality of features and characteristics of a medicinal product and its ability to satisfy stated and/or implied needs.

Quality Assurance  Definition: The sum total of the organized arrangements made with the object of ensuring that medicinal products are of the quality required for their intended use.

Quality assurance sections  GMP Section.  Documentation section.  Deviation section.  Quality Review section.  Internal Audit section.  Process validation section.

GOOD MANUFACTURING PRACTICE (GMP)  Definition: That part of QA which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use. Designed to minimize risks involved in any pharmaceutical production that cannot be eliminated through testing of final product.

GMP Principles  Must be built into manufacturing process.  Prevents errors that cannot be eliminated through quality control of finished product.  Ensures all units of a medicine are of the same (within specified parameters) quality.  Poor medicines leads to loss of credibility for everyone: manufacturers, health care workers and governments.

Good Manufacturing Practices are  Everyone’s responsibility (manufacturers, purchasers, distributors, consumers)  Clear, transparent, documented, readily observable  GMP are aimed at reducing risks inherent in pharmaceutical production  Qualification and validation provides confidence in manufacturers’ processes

Pharmaceutical layout

Documentation  definition: Documentation is the orderly presentation, organization and communication of recorded information to produce a historical record.

What is documentation  Each source of documentation tells a story about the specific item you are providing documentation for  It is a written record of events  It is documented evidence that steps were completed  It is a complete and accurate recording of processes, policies, and procedures that provides a historical record for future review  It is a reliable record that demonstrates that operations are in a state of control

What types of documents are legal documents in our industry  Log Books  Inspection Records  Discrepancy Reports  Temp/Humidity Data  Deviation Reports  Specifications  Complaints  Investigations  Work Instructions  SOP’s  Batch Records  Master Records  Change Control records  Preventive Maintenance Records

Why is Documentation Required?  The FDA requires documented information to prove that drugs are manufactured, packaged, held and distributed according to the FDA regulation.

Documentation requirements  All entries must be written in black or blue ink (indelible and non-erasable). Pencil is not allowed!  Time entries should indicate A.M. or P.M. time.  Data entries must include units of measure, units of measure should remain consistent throughout a record or logbook.  All blank spaces on controlled documentation should be N/A’.  Writing of a signature or initials other than your own is not allowed.

Documentation requirements  Signatures have different meaning depending upon the type of document you are signing. It could mean that you have(are):  - performed a task  - witnessed a task  - approving a document  - verifying information/document  - submitting information  - authoring a document

Documentation requirements  Error Correction When you make a correction on a document you should: a. use one single line to cross out the error. b. sign in next to the line corrected. c. write the date that you made the correction. d. explain why the correction is made.

Documentation requirements Is E-Mail Documentation?  E-mail can be used in court. Companies are required by law to backup computer systems and to retain the backups for a certain period of time.

Deviations

Definition  Departure from an approved instruction or established structure.  Any non-compliance of an established GMP standard or of approved requirements, specifications and standard operating procedures

Definition The deviations are:  Incident.  Out of specification or trend (OOS, OOT).  Complaint.

Examples for potential deviations in different areas  Machine defects.  System failures.  Temperature, humidity, number of particles or pressure differences outside of limits.  Deviations in microbiological monitoring.  Calibration results outside of limits.  Failure to keep calibration or maintenance intervals.  Regulations (SOPs).  Quality Control Confirmed OOS or OOT.  Storage.

Deviation Example Capping Definition: 'Capping' is the term used, when the upper or lower segment of the tablet separates horizontally, either partially or completely from the main body of a tablet and comes off as a cap, during ejection from the tablet press, or during subsequent handling. Reason: Capping is usually due to the air-entrapment in a compact during compression, and subsequent expansion of tablet on ejection of a tablet from a die.

Deviation Example Sticking Definition: tablet material adhering to the die wall. Reason: Improperly dried or improperly lubricated granules.

Deviation Example Twinning Definition: This is the form for tow tablets that stick together. Reason: Its a common problem with capsules shaped tablet. Remedies: Reduce the spray rate or increase the pan speed.

Phases in the systematic handling of deviations Phase Aspects Elements 1 Event documentation ● initial documentation 2 Description of problem ● first corrections, if applicable ● data collection 3a Failure investigation ● structured investigation into possible root causes 3b Root cause analysis ● test models, if applicable ● extension to other batches or products, if applicable ● reconciliation with risk management system 4a Risk assessment ● check on whether deviation affects other batches and products ● decision on whether action is required and if so, what actions must be taken 4b Specifying actions ● proposals for corrective and preventive actions, if applicable 4c Action approval ● examining and approving actions ● specifying test models and acceptance criteria for the test for effectiveness 5 Implementing the actions ● monitoring status 6 Test for effectiveness ● monitoring status ● currentness of risk assessment 7 Periodic review ● Risk Review ● Product Quality Review (PQR) ● Management

Classification of deviations Class Type of deviation Investigation Recording in system I no formal Trend Analysis ● No impact on safety or quality of the failure II product investigation CAPA System ● e.g. calibration outside of time interval III with corresponding results formal failure CAPA System ● Product suitable for marketing investigation ● Proof by additional investigations: no formal failure impact on safety or quality of the product investigation ● e.g. temperature deviations during storage ● product suitable for marketing ● impact on safety or quality of the product ● e.g. stability problems, OOS, non- compliance with filed specifications ● product not suitable for marketing

Example of a simple, standardized failure investigation report

Failure investigation * The following must be taken into consideration when searching for root causes:  Machines  Personnel  Materials  Environment  Processes

Root causes  If no clear root cause has been assigned, a probable cause must be determined. Appropriate grounds for this must be given. At least one of the following points is required to substantiate the root cause of the failure. ● observations recorded in the process ● documents from the unit, such as reports ● replication of the failure under comparable conditions

Corrections Describes the actions necessary to eliminate the existing deviation. Corrective actions Describes the actions necessary to eliminate the root causes of the existing deviation and to prevent its recurrence. * A correction can be made in conjunction with a corrective action

Preventive actions  Describe the actions that are necessary to avoid possible deviations or trends.

CAPA Effectiveness  the efficacy of the corrective action or preventive action must be tested (efficacy check) :  objective criteria to be specified to measure the result and outcome of the CAPA activities.  If the defined actions do not show the expected positive results, new corrective or preventive actions must be considered and decided upon , in the end this is a continuous, iterative process that should be repeated until it leads to a satisfactory result.

Verifying CAPA Effectiveness  Auditing (is used when the CAPA involves change in system) .  Spot check (is used for random observations of performance or reviews of record).  Sampling .  Monitoring (is used for real time observations over a defined period)  Trend Analysis (is the retrospective review of data to verify the expected results were achieved)  Periodic Product Review.

Thant you Any Question ? Prepared by: Eng. Mohammad Nazzal mnazzal [email protected]