Author: chandrasekhar Panda

Importance of Differential Pressure in Pharmaceutical


Differential pressure in pharmaceuticals helps to prevent contamination and cross-contamination. A Magnehelic gauge device is used to measure the pressure difference between the two adjacent sections. The gauge has two inlets point for the pressure that is connected to the area being monitored.

Differential pressure is the pressure that differentiates between the pressures of the atmosphere of one area (process area) to other surrounding areas (corridors). It is measured in pascals and wc of Hg. Magnehelic gauge is used to records the differential pressure.

Why is Differential Pressure important in Pharmaceuticals?

Differential pressure prevents contamination and cross-contamination during the product manufacturing process; during the process, the air becomes contaminated. If Differential pressure is not maintained within limits, the contaminated particles may enter or mix up with the fresh air and contaminates other manufacturing products.

Differential pressure must be checked and recorded every Two Hours ± 15 minutes in the manufacturing area where the product is directly exposed, and every Four Hours ± 15 minutes where the product is directly not exposed or as per the given SOP “Records of area Differential Pressure.”

WHO guidelines on Differential pressure

According to the WHO Guidelines annex 8, the airflow flow should be from a clean area to a cubicle area to avoid contamination. The processing area should be negative ( in the case of Oral Solid Dosage) compared to the corridor area to ensure airflow from the aseptic area to the non-aseptic area.

Generally, dust generates in the process area, so the corridor should be at higher pressure to stop dust flow in the corridor area.

Importance of the airlock in Differential Pressure

Airlock in pharmaceuticals is used to transfer the materials. It is advised to keep positive pressure in the corridor than the processing or manufacturing area. The positive airlock should be there to minimize direct airflow from process air to the Non-Process area, which helps control the direct contamination in the processing area.

Airflow Direction in the Non-sterile area with Respect to Corridor

keep negative pressure inside the controlled area(process area) as compared to the corridor area(positive pressure) to prevent cross-contamination.

Negative pressure means clean airflow from the corridor going into the process room, and contaminated air in the process area flows out from the riser’s filters. These types of air systems are suitable for OSD (oral solid dosage), steroids, and chemotherapy products.

Differential Pressure in a Sterile area with respect to Corridor

Cross-contamination of one product with the other products is an issue, but in a sterile area (injection filling), there are more chances of microbial contamination; that’s the reason positive pressure is maintained inside the sterile area as compared to the corridor.

Way to maintain Pressure in Area Recovery Test for HVAC  

It’s important to perform a recovery test as per the scheduled time to check the pressure differential in pharmaceuticals produced by the HVAC system. The calibration of the Magnehelic gauge must be checked regularly.

Building construction:

To take care of the integrity of the unit, airtight doors, a Gap between the door and floor, and window installation is required to stop the loss of pressure through the gap. An alarm for a sign should be available for workers to understand any loss of atmospheric pressure.

Types of audit in pharmaceutical industry


Introduction :

Audit is the examination or inspection of various books of accounts by an auditor followed by physical checking of inventory to make sure that all departments are following documented system of recording transactions. It is done to ascertain the accuracy of financial statements provided by the organisation.

This is the generic definition of an “audit”.

The keyword is “examination”. However, this definition of the term audit is very misleading in the pharmaceutical industry (drug substance, drug product, pharmaceutical formulation intermediates, medical devices, biological, veterinary medicine, Ayurvedic and homeopathy medicines), the definition need to be elaborated.

Quality audit is the process of systematic examination of a quality system carried out by an internal or external quality auditor or an audit team. Quality of a product is not “built in” in the laboratory. A quality culture has to be introduced into the organization. In simple words, quality is customer satisfaction and also compliance to minimum regulatory requirements based on the products. In India, the quality of pharmaceutical for the domestic market is controlled by the requirements as lead down in the Indian pharmacopoeia or national formulary and in many cases, specifications developed by the manufacturers known as “in house specification” (I.H.S). The permission to market any formulation, drug substance, API is granted by state FDA and CDSCO (Central Drug Standard Control Organization).On submission of the manufacturing data and quality test parameter. The team from the state FDA and CDSCO come down for an inspection in other words an audit. It is an important part of an organization’s quality management system and is a key element in the ISO quality system standard, ISO 9001.

The Drug and Cosmetics Act 1940 and Rules there under 2018, state that the manufacturing unit must have a quality control laboratory. The laboratory in itself along with the microbiology laboratory cannot control the quality. It can only assess the quality. The laboratory will require and additional tool to “assure quality”.

The laboratory should not be mistaken only for quality control but also include quality assurance. The tool for the personnel responsible for quality assurance is the audit. Conducting an audit or facing an audit is an integral function of quality assurance.

Quality audits can be integral part of compliance or regulatory requirements. One example is the US Food and Drug Administration, which requires quality auditing to be performed as part of its Quality System Regulation (QSR) for medical devices (Title 21 of the US Code of Regulations, part 820) and anything sold to the consumer. The ICH (International Conference for Harmonization) guidelines and also WHO (World Trade Organization) guidelines require audit to be conducted internally as a part of compliance to GMP (Good Manufacturing Practice).

The objectives of the audit either by internal assessment or external assessment are compliance to quality, documentation, and facility etc. to ensure a safe efficacious product is delivered 365 days 24 by 7.

Types of Audits:

ISO 19011:2018 defines an audit as a “systematic, independent and documented process for obtaining audit evidence [records, statements of fact or other information which are relevant and verifiable] and evaluating it objectively to determine the extent to which the audit criteria [a set of policies, procedures or requirements] are fulfilled.” There are three main types of audits namely Internal and External.

• Internal Audit:

Internal audit is carried out by a team of interdepartmental personnel at least twice a year to assess the compliance to quality management system and customer satisfaction.

The customer satisfaction is assessed by viewing return good documentation and customer complaints and regulatory recalls. This type of audit is an examination of the tool used to measure quality itself. An internal quality audit seeks to evaluate an organization’s Electronic Quality Management System (EQMS). The quality documentation and processes managed by the software solution are reviewed to ensure maximum efficiency and high-quality product outcomes.

The software manual is audited to ensure all critical areas of the solution are covered and all key employees readily have access to the document. Work instructions are audited to ensure conformity to standard operating procedures and to confirm quality processes are meeting targets.

Production Process Audit: Production team members usually get an examination (audit) when Operator Acceptance or Certified Operator programs are in place, or when skills management re-qualifications are required. Auditors evaluate changes to processes, evidence of training, past activity for escapes, non-conformance, and conformity inspections of operator accepted product as part of the re-qualification.

In pharmaceutical industry, there are many highly skilled operations in manufacturing area e.g.

  • Operation of tablet compression machine
  • Operation of Rapid Mixer Granulator
  • Strip & blister packing machines.
  • High speed automatic capsule filling machine
  • Operation of autoclaves etc.

Here, the desired skill of the operations is a must. These skilled must be evaluated and if needed the operations should be provided with necessary skill/operational training.

Safety Audit: A safety audit looks at the plans and procedures designed to protect the safety of company employees. This type of audit can include a review of equipment operation or an examination of organizational procedures to ensure routine safety. Successful safety policies prevent injuries and accidents from occurring and improve overall employee well-being.

Facility Audit: A facilities audit addresses quality concerns of a corporation’s assets. Components of a facilities audit can include a review of building systems such as HVAC, water system, manufacturing equipment or technology. Processes associated with these facilities are reviewed to ensure safety and identify improvements that could affect quality outcomes.

Facility and Equipment Validation comes to our help in seeing that every thing is in order FDA officials give very high importance to such facility and equipment validation activities. Audits can point out deficiencies in this area.

Risk Assessment Audit: A risk assessment is a process that identifies potential workplace hazards, and then categorizes each risk so preventative measures can be put into place. An audit of this type helps companies put an effective risk mitigation strategy into action. When all risks have been identified, preventative measures can be prioritized, preventing adverse workplace and economic consequences.

Product audit: This type of audit is an examination of a particular product or service, such as hardware, processed material, or software, to evaluate whether it conforms to requirements (i.e., specifications, performance standards, and customer requirements).

System audit: An audit conducted on a management system. It can be described as a documented activity performed to verify, by examination and evaluation of objective evidence, that applicable elements of the system are appropriate and effective and have been developed, documented, and implemented in accordance and in conjunction with specified requirements.

External Audit:

  • Customer Audits
  • Regulatory Audits
  • Vendor Audits
  • Laboratory Audits
  • Customer Audits: Any customer desirous doing business with pharmaceutical organization like to carried out a due diligence study of the QMS (Quality Management System) being followed.
  • Regulatory Audits: It is carried out either by the state FDA or CDSCO or WHO or any other international regulatory agency before they give a no objection certificate for manufacture and sale to that particular country of the pharmaceutical product, certifying that QMS is in compliance with minimum requirements. Regulatory audits are conducted to verify the data collection process is systematically reviewed to identify possible areas of non-conformance. Examples of regulatory agencies include international regulatory audits by USFDA, MHRA, TGA, MCC etc.
  • Vendor Audits: This audit is required before purchasing any raw material from any vendor to assess whether basic QMS and GMP are being followed. Vendor audits allow an organization to collaborate in real time directly with its suppliers. By auditing the supply chain, companies can control the quality of its suppliers and sub- tier suppliers and introduce accountability for poor performers. Key performance indicators (KPIs) quickly identify areas for improvement. With this level of transparency, suppliers are able to view purchase order activity such as receipt and inspection history in order to collaborate or non-conformance and corrective actions.
  • Laboratory Audits: Whenever sophisticated testing with instruments not available in the in house laboratory, the services of an external laboratory may be utilizing subject to the organization carrying out a comprehensive laboratory audit compliance to GLP (Good Laboratory Practice) and GDP (Good Documentation Practice) and GDIP (Good Data Integrity Practice). Laboratory audits should also look into the analytical methods validation documentations.

 Objectives of a Quality Audit :

Quality is always dynamic and never static. It is always on the move. Quality demands continuous improvement.

The objective is:

  • To determine the conformity or non-conformity of the quality system in meeting the specified requirements.
  • To determine the effectiveness of the implemented quality in meeting the specified Quality objectives.
  • To provide the audit team with an opportunity to improve the Quality system.
  • To meet the regulatory requirement.
  • To permit listing of the audited organizations Quality systems in a register.
  • Audits are intended to verify that manufacturing and control systems are operating under a state of control.
  • Audits permit timely correction of potential problems.
  • Audits can be used to establish a high degree of confidence to remain under an adequate level of control by managements.
  • Assess your document management system.
  • Evaluate your locations and any site-specific conditions.
  • Assess your understanding of the requirements of the standard.
  • Agree the scope of your Documented Management System, processes and location(s) and related statutory and regulatory aspects and associated risks.
  • Establish your planning arrangements for Internal Audits and Management Reviews.
  • Identify any areas for potential Improvement of the Management System.
  • Evaluate the implementation and effectiveness of your Management System.
  • Assess your performance against key performance objectives and targets (monitoring, measuring, reporting and reviewing).
  • Evaluate your legal compliance, operational control of processes, Internal Audits, Management Reviews and Policies.
  • Evaluate links between the normative requirements, policy, performance objectives and targets, responsibilities, competence of personnel, operations, procedures, and performance data.
  • Identify any areas for potential Improvement of the Management System.
  • Ensure your Management System has continued to fulfil requirements between Audits.
  • Ensure Internal Audits and Management Review has been performed to programme.
  • Review actions taken on nonconformities identified during previous Audits.
  • Evaluate your handling of any complaints.
  • Evaluate the continued effectiveness of the management system, with regard to achieving your objectives.
  • Evaluate your legal compliance and performance.
  • Evaluate your progress of planned activities aimed at continual improvement.
  • Ensure continuing operational control.
  • Review any changes to your organisation since the previous Audit.
  • Identify any areas for potential Improvement of the Management System.

GMP MODULES FOR PHARMACEUTICAL PRODUCTS BOOK


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Book Images

Media Fill Process


What is Media Fill

The Media fill or Broth fill technique is one in which a liquid microbiological nutrient growth medium is prepared and filled in a simulation of normal manufacturing operation.

The microbiological growth medium such as Soybean Casein Digest Medium (SCDM) is processed and handled in a manner which simulates “normal” manufacturing process with same exposure and possible contamination.

The final container is then incubated and checked for turbidity which indicate the microbial contamination.

Medium Selection

  • The medium should be able to support the growth of a wide range of microorganisms.
  • The medium should be suitable from a process perspective to perform as product (e.g. it should be filterable, if the product is normally also filtered).
  • The medium should be clear in order to be able to observe any turbidity caused by growth.
  • The medium should be prepared according to manufacturer’s instructions.
  • Medium tested on House Flora Meaning: House Flora determined as a prerequisite
  • Growth Promotion Property tests with the correct amount of microorganisms (10 – 100 or less CFU/unit)
  • GPP test performed either after processing or in parallel; growth within 5 days

Area General Principles :

  • Media fills should be performed in the same areas as product fills (this includes being in and out a freeze-­‐dryer, if applicable!).
  • If the same process is carried out in another clean room, this should also be validated.
  • Each filling line to be validated twice per year
  • Bracketing principles can be applied to reduce number of fills.
  • Worst case principles can be applied to reduce number of fills.

Filling Equipment’s General Principles :

  • The same equipment that is used for product fills should be used for media fills.
  • If inert gases are normally used in the process, filtered air should be applied during media fills not to prohibit growth of microorganisms. (If anaerobic microorganisms are found during routine E.M., the use of inert gases should also be considered.)
  • All aseptic holding vessels should be part of a regular process simulation test, unless a validated pressure hold or vacuum hold test is routinely performed.

Process General Principles :

  • The media fills should simulate the complete product fill situation as far as equipment, processes, Environmental Monitoring, personnel involved, areas and time taken for both filling and holding.
  • The media fill should represent a “worst case” situation compare to a normal fill with respect to manipulations and interventions.
  • If filling takes place for over 24 hours, the media fills should extend to the same time, unless the validity of the media fill is not compromised by running the fill for less time.

PLANNED INTERVENTIONS

  • Media fills should include all interventions normally expected during product filling.
  • Unplanned interventions should reflect actual experience with the filling process.
  • Simulating interventions defines the validated envelope– Excursions outside validated envelope, batch failure as default
  • Normal actions associated with the process, e.g. stopper bowl filling
  • Normal occurrences, e.g. needle exchange, line stoppage
  • Abnormal occurrences determined from deviations noted during previous runs
  • Operator versus allowable interventions by him/her to be defined
  • During normal operation, after intervention: removal of possible contaminated vials; that is allowable for Media Fill as well.
  • Only discarding of vials as it is usually done.

Media Fills Duration :

  • ISO: “sufficient duration to cover most manipulations”
  • EU: “sufficient to enable a valid evaluation”
  • PIC: “Over the whole of the standard filling period”
  • FDA: “Duration of commercial aseptic process best and preferred for larger simulations

PRIMARY PACKAGING COMPONENTS – GENERAL PRINCIPLES

  • Primary packaging components should be prepared as for regular production.
  • When normally opaque containers are used, these should be used for media fills as well. The examination of growth though should be performed by transferring the whole contents.

PRIMARY PACKAGING COMPONENTS – Point to consider

  • Primary packaging components should be the same as for normal production runs (amber vs clear vials?)
  • Primary packaging components should be prepared the same as for normal production runs (washing and sterilisation)
  • Media fill volume should be sufficient to cover, when the vial is inverted, the whole inner surface.

Frequency :

  • Start-­‐up simulation is applicable to new processes, new equipment or after critical changes to environment, equipment, process or significant personnel changes.
  • Start-­‐up simulation should consist of three consecutive, satisfactory runs with the same shift of people.
  • Ongoing simulations should happen normally twice a year per shift and per process (unless there were changes to the product process or action limits exceeded).

The Outcome :

  • Incubation is normally 14 days at 20 – 25ºC or sometimes 7 days at 20 – 25ºC followed by 7 days at a higher temperature (<35º C).
  • When inspecting for growth, a known sterile container should be used as comparison.
  • Alert and actions limits should be previously established.
  • Even if not alert nor action limit was exceeded, microorganisms should be identified.

Media Fills – OOS

  • There are not detailed indications from regulations, except:
  • Each contamination must be investigated.
  • Repeat media fill or repeat validation, after investigation, depending on the level of contamination and the run size.
  • There is not distinction between initial validation and routine revalidation

Media Fills—Points to consider in Summary :

  • Duration of longest run
  • Worst case environmental conditions
  • Number and type of interventions, stoppages, adjustments, transfers
  • Aseptic assembly of equipment
  • Number and activities of personnel
  • Number of aseptic additions
  • Shift breaks, changes, multiple gownings
  • Number/type of aseptic equipment disconnections and connections
  • Aseptic samples
  • Line speed/configuration
  • Manual weight checks
  • Operator fatigue
  • Container/Closure types run on the line
  • Temp/Relative humidity extremes
  • Conditions permitted before line clearance

HPLC Troubleshooting


General Pattern:

  • Locate the problem by ranking possible causes.
  • Verify the presence of the most probable cause.
  • If present – fix the problem, otherwise verify the existence of the next possible cause.

First try to distinguish System problem or Method Problem

HPLC System Components

  • Pump
  • Injector/ Autosampler
  • Column
  • Detector
  • Data System/Integrator

Method vs. System Troubleshooting

System Parameters

  • Flow stability
  • Backpressure
  • Clogging
  • Detector problems
  • Injection suitability

Method Parameters

  • Flow rate
  • Eluent composition
  • pH &pH modifier (type)
  • Injection volume
  • Temperature
  • Gradient profile

System Parameters

Simple preliminary verification of system setup can save time

SolventDegasserPumpAuto samplercolumnDetector
Bottle fill-in Inlet filter dateFlush if solvent change >15 mLBack pressure Flow stability Check-valvesVial fill-in connections cross-contaminationColumn type connectionsWavelength

Categories of Column and System Problems

  • Pressure
  • Peak shape
  • Retention
  • Detection

I. Pressure Issues

Column observationsPotential Problems
High pressurePlugged frit
Column contamination
Plugged packing
Low pressureLeak
Flow Incorrect

Determining the Cause and Correcting High Back Pressure

Many pressure problems are due to blockages in the system.

If Column pressure is high:

  • Back flush column – Clear “dirty” frit surface
  • Wash column – Eliminate column contamination and plugged packing
  • – high molecular weight/adsorbed compounds
  • – precipitate from sample or buffer

Column Cleaning

Flush with stronger solvents than your mobile phase

Use at least 25 mL of each solvent for analytical columns

Reversed-Phase Solvent Choices in Order of Increasing Strength

  • Mobile phase without buffer salts
  • 100% Methanol
  • 100% Acetonitrile
  • 75% Acetonitrile:25% Isopropanol
  • 100% Isopropanol
  • 100% Methylene Chloride*
  • 100% Hexane*

* When using either Hexane or Methylene Chloride the column must be flushed with Isopropanol before returning to your reversed-phase mobile phase.

Prevention Techniques for column problems

Use column protection

  • In-line filters
  • Guard columns
  • Filter samples
  • Filter buffered mobile phases
  • Sample clean-up (i.e. SPE)
  • Appropriate column flushing

II.           Peak Shape Issue

What Are Common Peak Shape Issues?

  1. Split peaks
  2. Peak tailing
  3. Broad peaks
  • Many peak shape issues are also combinations – i.e. broad and tailing or tailing with increased retention
  • Symptoms do not necessarily affect all peaks in the chromatogram
  • Each of these problems can have multiple causes

Peak Splitting Caused By Disrupted Sample Path

  • Flow Path Disrupted by Void
  • Sample Allowed to Follow Different Paths through Column
  • Poorly Packed Bed Settles in Use
  • High pH Dissolves Silica

Split Peaks from Column Contamination

Column: Stable Bond SB-C8, 4.6 x 150 mm, 5 μm Mobile Phase: 60% 25 mM Na2HPO4, pH

3.0 : 40% MeOH Flow Rate: 1.0 mL/min

Temperature: 35°C Detection: UV 254 nm Sample: Filtered OTC Cold Medication:   

1.Pseudoephedrine 2. APAP 3. Chlorpheniramine

Peak Tailing, Broadening and Loss of Efficiency

May be caused by:

  • Column “secondary interactions”
  • Column contamination
  • Column aging
  • Column loading
  • Extra-column effects

Peak Tailing – Column Contamination

Trick: Reverse Column and Run Sample –If Improved, Possible Cleaning Will Help -No improvement-Column Damaged and Needs to be Replaced

Peak Shape: Fronting Peaks

Symmetry < 0.9

Causes: Column Overload

Peak Shape: Broad Peaks

All Peaks Broadened:

  • Loss of Column Efficiency.
  • Column Void.
  • Large Injection Volume

Some Peaks Broadened:

  • Late Elution from Previous Sample (Ghost Peak).
  • High Molecular Weight.
  • Sample – Protein or Polymer.

III.   Changes in Retention Time

Changes in Retention Can Be Chemical or physical May be caused by:

  • Column aging
  • Column contamination
  • Insufficient equilibration
  • Poor column/mobile phase combination
  • Change in mobile phase
  • Change in flow rate

Mobile Phase pH and pH Buffers Why Are These So Important in HPLC?

pH Effects Ionization

  • Silica Surface of Column
  • Sample Components of Interest

Buffers

  • Resist Changes in pH and Maintain Retention
  • Improve Peak Shape for Ionizable Compounds

Effects Column Life

  • Low pH strips Bonded Phase
  • High pH Dissolves Silica

Importance of pH and Buffers

  • pH is an effective tool for adjustment of selectivity and retention
  • pH can be used to optimize the resolution
  • Reversed phase packaging are most stable between pH’s 2 – 8.
  • Don’t Forget – Match Column to pH of mobile phase for maximum column lifetime.

IV. Detection Issues

Recognize Where the Problem Originates

  • Is it a consequence of technique?
  • Is It expected due to use of certain mobile phase components?
  • Can it be corrected by adjusting detector parameters?

Drifting Baselines

  • Detector (UV) not set at absorbance maximum but at slope of curve
  • Gradient Elution
  • Temperature Unstable (Refractive Index Detector)
  • Contamination in Mobile Phase
  • Mobile Phase Not in Equilibrium with Column

Baseline Noise

Ø  Mobile phase contaminated, deteriorated, or prepared from low-quality materials
Ø  Mobile phase solvents immiscible
 
Ø  Air trapped in system
 
Ø  Air bubbles in detector
 
Ø  Detector cell contaminated (even small amounts of contaminants can cause noise)
Ø  Weak detector lamp

Conclusions

HPLC column problems are evident as

  • High pressure (prevention better than the cure)
  • Undesirable peak shape
  • Changes in retention/selectivity

Often these problems are not associated with the column and may be caused by instrument and chemistry issues.

  • pH of mobile Phase
  • Instrument Connections
  • Detector Settings
  • Metal Contamination