Pharmaceutical Manufacturing Controls

Manufacturing & Packaging Controls

• Good manufacturing practices (GMP) should be followed during all manufacturing operations, including control measures.
• Four key factors are vital: Identity, Strength, Safety, and Purity, ensuring the efficacy of the pharmaceutical product.

Introduction - Identity

• Identity refers to correctly identifying products, personnel, materials, machines, equipment, and locations for manufacturing operations.

Introduction - Strength

• Strength refers to the precise concentration of the active substance in each unit of the finished pharmaceutical product.

Introduction - Safety

• Safety primarily means the safety of consumers of the product.
• Safety also involves the safety of the people who produce the products.
• Manufacturing operations should be safe, alongside the safety of the final product.

Introduction - Purity

• Purity represents freedom from cross-contamination and mix-ups.

Introduction - Achieving these things

• Manufacturing operations must be supervised by qualified technical staff (Industrial pharmacists, chemists, microbiologists).
• Operators and workers need appropriate training, knowledge, skills, and attitudes for their responsibilities.

Introduction-Materials

• All materials must be clearly labeled at each stage, specifying details like name, status, batch numbers, and quantity.
• These materials must be protected throughout the manufacturing process from contamination.
• Stability also needs maintaining.

Introduction-Containers and equipment

• All containers and equipment must be identified and cleaned to the accepted standards.
• Records of cleaning, operations, and maintenance should be maintained.

Sanitation of Manufacturing Premises

• Manufacturing areas should be clean and sanitary.
• Areas for dust, debris, and waste collection in processing areas should be marked.
• Containers for waste should be readily available, made from suitable materials like plastic or stainless steel.
• Collected trash should be removed at regular intervals.

Sanitation of Manufacturing Premises - Cleaning and disinfecting

• Validated cleaning and sanitizing procedures should be used to maintain cleanliness and sanitation in the factory.
• Cleaning involves using detergents and disinfectants.
• SOPs for facility cleaning should specify the detergent, concentration, frequency, method, and responsible individuals.

Sanitation of Manufacturing Premises - Records

• Records of cleaning activities, including date, time, and personnel involved should be maintained.

Mix-Ups and Cross Contamination - Definitions

• Mix-ups occur when undesired materials enter desired materials (e.g., tablets of different products, products in wrong cartons).
• Contamination occurs with materials not wanted, even if unseen (e.g., fine dust).

Mix-Ups and Cross Contamination - Sources

• Sources include materials, people, machines, and processing areas.
• Improper handling, broken containers, uncontrolled activities can cause contamination.

Mix-Ups and Cross Contamination - People

• People working in processing areas are a significant source of contamination.
• Such people must adhere to protocols (trained, restricted movements, using protective gear, medical checkups) to prevent contamination.

Mix-Ups and Cross Contamination - Additional

• Individuals with infectious diseases or open wounds should not work in processing areas.
• Staff should immediately inform supervisors of illnesses that could affect product quality, particularly concerning aseptic areas.

Mix-Ups and Cross Contamination - Machines and equipment

• Machines, equipment, and related activities are considerable contamination factors.
• All equipment must be clean and covered when not in use.
• Discharges (dust, smoke, etc.) must be controlled.

Mix-Ups and Cross Contamination- Further measures

• Monitoring contamination by using systems like dust collection or water/solvent scrubbing.
• Maintaining records for cleaning and sanitation.

Mix-Ups and Cross Contamination - further measures

• Manufacturing areas should be categorized by cleanliness levels (aseptic filling, non-sterile).
• Thorough and validated cleaning and sanitizing SOPs must be implemented.
• Cleaning records must be kept.

Mix-Ups and Cross Contamination - Controls

• Exhaust systems, air filtration, closed material handling, and separate air handling units help control contamination.
• Different air pressure zones (positive/negative) in different rooms should be implemented based on product types.
• Segregated areas for high-risk products (e.g., penicillin, live vaccines).

Mix-Ups and Cross Contamination - additional measures

• Personnel must wear protective clothing in high-risk areas.
• Cleaning and decontamination procedures (proven effectiveness) to prevent cross-contamination from equipment.
• Staff training in GMP principles to avoid mix-ups and cross-contamination.

Mix-Ups and Cross Contamination - Packaging

• Packaging lines in central packaging areas should be separated (at least 1.2-1.5 m).
• Similar products should be prevented from being processed or packed consecutively.
• Maintaining SOPs and records for checking packaging line clearance before each batch.

Mix-Ups and Cross Contamination - Area Clearance/Machine Clearance

• Documents to record and verify area/machine clearance for further processing, and including re-cleaning.

Packaging Operations

• Packaging should follow precautions (similar to manufacturing).
• Prevent cross-contamination.
• All packaging equipment and lines should be cleaned between batches.

Packaging Operations - Line Clearance

• SOP with records for packaging line clearance maintaining absence of previous batch material.

Packaging Operations- Labelling and packing

• Proper and timely labeling and final packing are essential to prevent mix-ups.
• Clearly plan and segregate overprinting activities.
• Quality and durable labeling is important and should be visible.
• Follow labeling guidelines, including time frames.
• Use of a suitable drying ink (or other appropriate method) will reduce mix-up risks.

Packaging Operations -Additional Control

• Use of empty packet detection systems (for tabs/caps).
• Online packaging checks for defects in appearance, completeness, correct materials, correct labels, and weights.

Packaging Operations - Further aspects

• Records for unusual events in packaging (investigations, vigilance).
• Thorough reconciliation of packaging materials and quantities before product release.
• Unused materials (that are discarded) must have proper disposal records.

Production of Intermediate and Bulk Products

• Raw materials are processed into packaging-ready bulk goods.
• Identity, strength, safety, and purity checks are vital.
• Before processing, materials must be verified for identity and quantity.

Production of Intermediate and Bulk Products - Procedures

• Areas and equipment must be clean.
• Pipelines, equipment, and other related tools should be checked and cleaned to eliminate any contamination risks.
• Environmental factors (temp, humidity, etc.) must meet the processing requirements.

Production of Intermediate and Bulk Products - Process Measurements

• Yield of materials throughout processing should be checked and compared with theoretical predictions.
• All measuring, weighing, and control equipment must be calibrated.
• Records of calibrations are maintained.

Production of Intermediate and Bulk Products - Further Considerations

• Repairs and maintenance activities should not jeopardize product quality.
• All specified IPQC checks must be performed at pre-determined points.
• Specialized areas and equipment are needed for medicinal products.

IPQC in Manufacturing - General Guidelines

• Having detailed SOPs is essential for in-process quality control.
• Critically examining steps and establishing specifications is necessary.
• Data from various manufacturing tests (e.g., assay, moisture, bulk density) is needed.

IPQC in Manufacturing - Further guidelines

• Check physical parameters for compression tablets (weight, hardness, friability).

• Collect data on fill weights, volumes, or the pH of solutions before finishing.

• Essential to monitor environmental conditions (temperature, humidity, etc.).

IPQC in Packaging

• Continuously monitor packaging lines for packaging integrity

IPQC in Packaging - Procedures and Automated Control Measures

• Use of tabulated checklists and competent personnel to verify and sign the checklists.
• Regular inspection and validation of automated controls and monitors.

IPQC in Packaging - Online Product Control

• Online monitoring of general appearance (of products), physical defects, weights, volumes, quantity, components, and materials used.

IPQC in Packaging -Further aspects

• Recording sample collection for testing procedures.
• Maintaining appropriate records of environmental conditions during processing.

Release of Finished Products

• Finished products are released for commerce after processing

Release of Finished Products - Conditions

• Placement of products into quarantine (with documentation completed) to prevent unexpected or improper product removal.
• An audit by quality assurance (to check and reconcile documentation) is essential before release.
• The QA department authorizes product release.

Process Deviations

• Deviations from predefined procedures (process deviations) are a possibility.
• Such variations should be avoided whenever possible.
• Exceptionally, if deviations are mandatory, they must be justified and recorded properly.

Process Deviations - Further Measures

• Frequent deviations require thorough investigation and potential modifications to the procedures using change control.

Time Limitations on Production

• Pharmaceutical production processes have specific time limits.
• Minimizing production time periods/lapses between stages.
• Proper and defined time limits/holds for intermediate stages (holding times).
• Documentation of deviations and any potential dangers caused by holding times.

Time Limitations on Production - Further Considerations

• Critical stages, the importance of holding times, and stability of each product must be clarified and documented accordingly.
• Detailed information must be available to the pharmacist or in the BPCR.

Expiration Dating - Principles (General aspects)

• Pharmaceutical product potency and effectiveness must be maintained till the expiration date.
• The expiration date depends on stability studies and the required product conditions.
• Detailed SOPs for stability studies.

Expiration Dating

• Data from stability studies must be used to determine the expiration date.
• Any storage conditions must be included in the labeling.

Expiration Dating - Additional guidelines

• Products that need reconstitution at dispensing time: should have expiration information for both the reconstituted and un-constituted forms.
• Packaging for products that must be used after opening.

Calculation of Yield

• Actual yield must be calculated and recorded. Theoretical vs. actual yields help determine efficiencies.
• The appropriate stages should be identified to calculate theoretical yield.

Calculation of Yield - Further Aspects

• Any deviation from expected yields must be investigated and the reasons recorded.
• SOPs should be established for theoretical and actual measurements.

Production Record Review - Fundamental Aspects

• The principle of cGMP implies that product quality is built-in, not just tested at the end.
• Quality control tests have limitations (like sterility tests).

Production Record Review (Quality Assurance aspects)

• QA verifies the entire production process, ensuring it followed the prescribed procedures.
• QA includes steps such as carrying out in-process quality checks, collecting samples throughout the process, and verifying all production-related documents.

Production Record Review - Quality Control Measures

• Review records related to the batch(e.g., quality records) alongside production-related documents.
• QA personnel should approve all production records before release.

Production Record Review - Further aspects

• Any unexplainable discrepancy about production batches must be thoroughly investigated.
• The investigation must include other related products (batches).
• Records for the investigation must be maintained and should include conclusions.