ICH, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use in its Chapter Q7, Good Manufacturing Practices (GMP) for Active Pharmaceutical Ingredients (API) laid down a structured set of activities for manufacturing the drug API.
Though the headings are directly referred from the guideline, these are just key extracts of good manufacturing practices.
Introduction to Good Manufacturing Practices
These guidelines are intended to assist and ensure that APIs meet the requirements for Quality and Purity. Manufacturing term is defined for every activity from the truck to truck and gate to gate.
This includes material receipt, production, packaging, labeling, quality control, release, storage, and distribution of APIs.
According to the guideline, “should” indicates recommendations expected to apply unless otherwise justifiable.
API Starting Material is a raw material or intermediate which structures API. Also, the API starting material can be purchased from contract manufacturers or suppliers or produced in-house.
The guideline is applicable to the manufacturing of APIs and their use in medicinal products related to humans. In that, APIs manufactured by chemical synthesis, fermentation, or any combination of these methods.
Following things goes out of the scope from this guideline as to the individual manufacturers and the local governing bodies responsible to take care of.
- Safety aspects
- Protection of environment
- Registration, Pharmacopeia requirements
- Whole Cells
- Blood and Plasma or their derivatives
- Gene therapy APIs
- Medical gases
- Bulk Packaged drugs (Final Medicinal Product)
- Steps involved prior to the introduction of the defined API starting material.
- Written responsibilities of all personnel specified prior to starting work
- Adequate number of personnel with proper qualification and training or experience
- Qualified individuals carry out regular training sessions about their role and good manufacturing practices.
- Should wear clean clothing suitable for production activities.
- Should wear protective apparels including head cap, face masks, hand gloves, and gowning as and when required.
- Should practice good sanitation and maintain good health habits to meet good manufacturing practices.
- Should avoid direct contact with the starting materials, intermediates, and API.
- Smoking, eating, drinking, chewing, and storing food should be restricted in certain designated areas apart from manufacturing areas.
- Personnel suffering from illness or open wounds in the exposure of the body should not engage in manufacturing-related activities. They should resume upon receiving clearance certificate from authorised doctor for any healthcare provider.
- Quality is the responsibility of all involved in manufacturing. Therefore, every manufacturer should establish, document, and implement an effective Quality Management System (QMS) with a systematic hierarchy.
- This QMS should ensure that API will meet its predetermined specifications for quality and purity.
- For that, independent Quality department/s apart from Production should be established such as Quality Assurance and Quality Control with a defined set of responsibilities.
- Specified personnel with activities involving release or approval of intermediates or APIs. No material release or use prior satisfactory completion of the evaluation by respective Quality Department unless otherwise justified.
- Any deviations or non-conformance from established procedures should be documented and explained. Critical deviations should be investigated with conclusions should be recorded.
- Should follow Good Documentation Practices (GDP) as part of Good Manufacturing Practices
- Should have the procedures for reporting regulatory inspections, deficiencies in good manufacturing practices, and product defects to the management in a timely manner.
Role of Quality Units
- Should review and approve appropriately quality-related documentation
- Releasing and rejecting intermediates or APIs for use outside the control of the manufacturing plant
- Reviewing and addressing approval requirements for completed Batch Manufacturing Records (BMR) and Lab control records prior to the release of API for distribution.
- Approving all procedures impacting the quality of intermediates or APIs
- Ensuring regular internal audits performed
- Ensuring critical deviations investigated and resolved
- Approving contract manufacturers
- Approving change control documents
- Reviewing and approving all qualification and validation documentation
- Ensuring investigation of quality-related complaints and their resolution
- Ensuring raw materials tested appropriately tested and results reported
- Ensuring stability data to support retest or expiry dates
- Periodically performing product quality reviews and ensuring adherence to the good manufacturing practices
- Preparing, reviewing, approving, and circulating the instructions for the production of intermediates or APIs as per documented procedures.
- Production as per BMR and approved procedures.
- Reviewing BMRs and logbooks.
- Ensuring 100% reporting of occurred deviations or non-conformances. Also recording investigation and conclusion.
- Ensure proper cleaning and sanitization of the production facility.
- Ensuring proper maintenance and calibration activities of equipment and instruments with records.
- Ensuring Qualification or Validation related documentation is prepared or reviewed and approved as and when required.
- Audit findings and corrective actions should be documented and notified to the responsible management.
- Agreed corrective actions should be implemented and completed in a timely and effective manner.
Product Quality Review
- Review of critical In-process control and API test results
- Review of investigations
- Review of failed batches
- Review of change controls, deviations, and non-conformances
- Review of stability and hold time study data
- Review of quality-related complaints and recalls
- Evaluation of corrective actions
Buildings and Facilities
- Location, Design, and Construction should promote cleaning, maintenance, minimal contamination, and operations.
- Should promote proper allocation of equipment and material placement with personnel and material movement to prevent cross-contamination and mix-ups.
- Should allow designated places for Receipt, Sampling, Testing, Quarantine, Holding, Storage, Production, Packaging and Labelling, and Laboratory related operations.
- Sufficient clean washing, showering, changing clothes, and toilet facilities close to production areas should be provided for personnel with cold and hot water, soap, air dryers, or single-use napkins facilities.
- Labs and Quality units should be separated from the actual production facility except for in-process quality checks.
- Process water should meet at minimum WHO Potable water requirements unless otherwise justified (potable equivalents drinking).
- If the water requires treatment prior to use in API manufacturing, it should be validated and qualified with action limits.
- If non-sterile API intends to be used in sterile formulations, water used in the purification process should be controlled for Bio-burden and Endotoxins.
- Only qualified utilities should be brought into contact with the intermediates or APIs such as Steam, Process Air, HVAC, etc.
- Proper ventilation to eradicate contamination or cross-contamination should be considered while designing HVAC ducting and air filtration systems.
- Pipelines with proper identification should be marked to avoid risks and hazards.
- The number of drain points should be adequate with dedicated drain lines with air brakes to avoid back-draw off.
- Not too bright not too dark, adequate light should be provided for easy visibility, maintenance, cleaning, and operations.
Sewage and Water Disposal
- Proper disposal mechanisms should be considered for sewage, solid waste, or liquid by-products inside the premises and immediate surroundings.
- Containers, location, and isolation of the wastes should be properly identified with labels.
- Separate facilities should be considered for highly toxic or carcinogenic Intermediates or APIs
Sanitation and Maintenance
- Written procedures for sanitation including cleaning schedules, methods, and equipment under cleaning, cleaning agents should be employed.
- Rodent bait stations with insecticides, rodenticides, fungicides, and fumigating agents should be considered for specified procedures to prevent contamination.
Design and Construction
- Suitable equipment sizing and material of construction should be considered for intermediates or APIs in scope.
- Equipment surfaces should be designed such that they don’t alter the quality of the product.
- Equipment should only be used in its qualified and validated operating range.
- All equipment and process lines should be properly labeled for identification.
- All process operations should be considered to operate in closed conditions unless otherwise justified.
- Consumables such as lubricants, heating, or cooling media should not contact the intermediates or APIs such that the quality of the product is altered or compromised.
- All drawings set should be maintained for each equipment
Equipment Cleaning and Maintenance
- A clear and precise preventive maintenance plan should be established with schedules and procedures.
- Procedures should be established for equipment cleaning with frequency and sufficient details which are reproducible and effective.
- Equipment should be sterilized as appropriate to prevent contamination.
- If certain equipment is utilized to manufacture the same intermediate over a period of the campaign, cleaning should be done at appropriate time intervals (i.e. batch to batch cleaning) to prevent product build-up and carry over.
- Acceptance criteria for residue should be described and justified.
- The status of the equipment should be labeled indicating cleanliness and operation.
- Instruments critical to assure the quality of intermediates or APIs should be calibrated according to laid down procedures and schedule.
- Calibrating instruments should be traceable to certified standards unless otherwise justified.
- The current status of calibration should be identifiable and verifiable.
- Only calibrated instruments should be used.
- Computer-related systems involved in good manufacturing practices should be validated depending on complexity and criticality.
- Commercial software openly available in the market should not require the same level of testing. If it is not validated at the time of installation, a retrospective approach could be conducted as per available documents.
- Access levels should be properly assigned to the system to avoid unauthorized access. Also, the system should meet Audit trail requirements.
- Procedures should be in place for the operation and maintenance of the system.
- Critical data entry checks should be considered for accuracy and reliability.
- Modifications if required, should be followed with change control procedures and recorded.
- Back-up and restore features should be considered in case of a disaster or system failure and whenever data loss can occur.
- The written procedure should be considered for: Receipt, Identification, Storage, Quarantine, Sampling, Handling, Testing, Approval, Rejection, Distribution, and Disposal.
- A list of critical material suppliers should be readily available at the manufacturing location.
- If the supplier is not the manufacturer of the critical material, the name and address of the manufacturer should be in the records.
- Changing the material critical to intermediate or API should be followed as per change control procedures.
Receipt and Quarantine
- Once received and prior to acceptance, material container/s should be visually examined for correct labeling, damage, broken seals, and evidence of tampering or contamination.
- Materials should be held under quarantined till they are tested and released for use.
- Prior to mixing the newly arrived containers released after testing with the existing stock, procedures should be available to prevent discharging incoming material wrongly into existing stock.
- Each container of material should be assigned and identified with a unique code, batch, or receipt number.
Incoming Material Sampling and Testing
- Verification of the identity of each batch of material should be conducted with at least one test except processing aids, hazardous or highly toxic raw materials if the manufacturer’s Certificate of Analysis conforms to established specifications.
- Supplier or manufacturer should provide evidence that specifications meet as per evaluation. Also, regular verification of the Certificate of Analysis (COA) should be performed for reliability.
- Sampling methods and samples should represent a complete batch with sampling locations, the number of containers, and sampling quantity. For this, a proper sampling plan should be in place considering criticality, quality, variations, and analysis quantity.
- Sampling methods should be contamination-free for both sampled material as well as remaining material.
- Apart from that, clear statements on the label of the respective container should be marked for identifying the sample removal.
- Dedicated storage areas should be considered for avoiding contamination and cross-contamination. Also, they should promote proper cleaning and inspection.
- Fiber drums, boxes should be kept off the floor.
- Storage area conditions should be properly maintained as required for the sustainability of the material.
- Order of the material should follow FIFO (First In First Out) basis such that oldest is used first.
- Storage of rejected materials should be marked and quarantined for avoiding accidental use.
Documentation and Records
- Documents that relate to APIs or Intermediates manufacturing, should be prepared, reviewed, approved, and circulated as per predefined procedures either hard copy or electronically.
- Issuance, revision, superseding, and removal of all documents should be controlled with history.
- All documents should be assigned with a retention period as per requirement.
- All documents and records should be retained for at least 1-year post expiry date of the batch. For APIs with a retest date, records should be retained for at least 3 years after the batch distribution is complete.
- Document entries should be indelible immediately after the activities are completed with signs and date. Corrections should be signed and dated leaving the original entry readable.
- Electronic signatures if used, should be implemented with secure authentication.
Equipment Cleaning and Records
- Equipment records should capture date, time, personnel, activity, product, and batch number for cleaning, manufacturing, sanitization, sterilization, and maintenance.
- If dedicated equipment used to manufacture the same intermediates or APIs in traceable sequence, separate records are not obligatory.
Master Product Instruction
- Master production instructions for each intermediate and API should be prepared, dated, and signed by one person and independently checked, dated, and signed by a person in the quality unit.
- Name of intermediate or API under the scope
- List of Raw Material
- Production location and major production equipment to be used
- Ratio and quantity of each raw material with a unit of measurement
- Process parameter ranges
- Sampling instructions and in-process controls with acceptance criteria
- Cycle times
- Expected outputs at different stages
- Storage, Label, and Packaging material specifications and instructions with a shelf life
Batch Production Record or Batch Manufacturing Record (BPR or BMR)
- Complete information related to production and control of records for each batch.
- Before issuance review should be done for the correct version number.
- Should be numbered with the unique batch identification number, signed and dated when issued.
- While performing continuous production, product code with date and time can be used as a unique identifier till the final number allocation.
- Date and Time for completed activities
- Identity of major equipment
- Actual results recorded for critical process parameters
- Sampling activities
- Signatures for the person performing, checking, and reviewing the activities
- Yield calculations at different stages of production
- Description of packaging and label
- Deviations if any, evaluation and subsequent investigation
- Written procedures for the investigation of critical deviations or non-conformances.
Laboratory Controlled Records
- Sample description with name, batch number, product code, date of sampling, quantity, and sign
- Cross-reference data for preparing required testing solutions
- Raw data generated during testing including graphs and charts
- Calculations performed related to required tests based on which conclusion of a pass or fail obtained
- Sign and date of testing quality unit personnel
- Periodic calibration of testing instruments
- Out of Specification (OOS) investigations
- Before a batch is released or distributed, written procedures should be established to review and approve records.
- Deviations, investigations, and OOS report should be reviewed as part of batch record review prior to batch release.
Production and Process Controls
- Weight measurement for raw material should not alter the quality of the material and measuring instruments should be checked for their accuracy and calibration.
- Materials should be identified with the name or item code, control number, quantity, and retest dates as appropriate.
- Actual yields should be compared with expected yields at designated steps during production. Also expected yields should be assigned with tolerance based on lab, pilot-scale, or manufacturing data.
- If the actual yield does not meet the expectations, the deviation should be initiated and investigated to determine the potential impact on the quality of the batch.
- Equipment status should be identified either through the status label on equipment or documentation, control systems, or as justifiable.
- Reprocessing materials should be segregated to avoid unauthorized use.
- Procedures should be established to monitor the progress of the batch at different processing steps which can cause quality variations.
- Acceptance criteria for in-process sampling should be based on development studies or historical data.
- Stringency for in-process control varies as less stringent at early stages while more stringent at the final stages.
- Qualified production personnel should perform in-process controls without quality unit approval if tunings are made within pre-established limits approved by Quality unit (s).
- Sampling practices should be contamination-free.
- Procedures for maintaining the sample quality after the sample has been collected should be established.
- OOS investigations are not typically necessary for in-process tests that are performed to monitor or adjust the process.
Blending Intermediates or APIs
- Blending is the process of combining materials with the same specification to produce a homogenous intermediate or API.
- Remember, in-process mixing of fractions from single batches or combining fractions from several batches for further processing is considered to be part of the production process and not the blending process.
- OOS batches should not be blended with other regular batches which are meeting appropriate specifications.
- Acceptable blending operations include but not limited to
- Blending of small batches to increase the batch size
- Blending of stakeouts (very small quantities of isolated material) to form one batch
- Post blending should be tested for conformance to established specifications as appropriate.
- Separate batch records should be considered for blending to ease the traceability of the blended batch from individual batches.
- The blending process should be validated if APIs are required for Oral Solid Dosages or Suspensions to demonstrate homogeneity of the combined batch including testing of critical attributes such as stability, particle size distribution, bulk density, and tap density as appropriate.
- The expiry date or retest date of the blended batch should be based on the manufacturing date of the oldest batch or tailings in the blend.
- Production operations should prevent contamination of intermediates of APIs by other materials, especially during the purification process stages.
- Residue carry-over from the same intermediate from the previous batch to the next batch can occur even if there are adequate controls. In such cases, the residue should not result in carrying degradants or microbes with it which can alter the established purity profile of the API.
- Written procedures should be considered for elaborating sampling, testing, approval, and rejection of materials, and record and storage of data.
- Scientifically sound sampling plans and test procedures should be considered to ensure raw materials, intermediates, APIs, labels and packaging materials conform to established standards related to quality and purity.
- Test procedures should be reliable to those described during the registration and filing of drugs.
- Specifications, sampling plans, test procedures should be approved by a quality unit including control of impurities, action limits, and objectionable organisms.
- Any OOS should require analysis and assessment of data for potential problems.
- Reagents and standard solutions should be marked with the last date of use.
- Primary reference standards should be documented and maintained as per the supplier’s recommendation.
- Wherever primary reference standard not available from an officially recognized source, an in-house primary standard should be established with appropriate documentation.
- Secondary reference standards should be prepared, identified, tested, approved, stored, periodically requalified as per written protocol.
Testing Intermediates and APIs
- Typical batch produced by a specific controlled production process should have established impurity profile for each API including retention time, range, and classification.
- For biotechnological-related impurities, refer to ICH Q6B.
- Actual impurity profiles should be compared to the ones submitted for regulatory considerations or historic data to detect the changes in API due to modifications in raw material, process steps, or equipment.
Certificate of Analysis (COA)
- For intermediates or APIs with an expiry date or retest date, they should be provided on the label as well as COA.
- Information on COA should also include, grade, batch number, date of release, tests performed according to requirements, acceptance limits, and results attained.
- COA should be signed and dated by authorized personnel of the quality unit. Also the name, address, and contact details of the manufacturer.
- For new COAs issued on behalf of contract processing, COA should include the name, address, and contact details of the contractor with reference to the name and address of the original manufacturer.
- Documented, validated stability-indicating test procedures should be considered while monitoring stability data.
- Samples of stability should be stored in the same material which is used for market containers.
- Generally, the first three commercial batches should be considered for the stability monitoring program to confirm the retest and expiry dates. After that, at least one batch per year of API manufactured should be added to the monitoring program and should be tested annually so on for stability.
- For shorter shelf-lives, such as biotechnological products which have one-year shelf-life, should be tested monthly for the first three months and after that at three months’ interval.
- Samples should be retained for one year after the expiry date of the API batch and for three years after the batch is completely distributed to evaluate the potential failure of the batch.
- Samples should be stored in the same packaging as well as storage conditions in which the API is stored or advanced.
- A sufficient number of samples should be retained to allow proper compendial analysis as appropriate.
Expiry and Retest Date
- These dates should be based on the evaluation of data derived from stability studies. Retest dates are commonly practiced than expiry dates.
- A representative sample should be collected for performing a retest.
Packaging, Identification and Labelling of APIs and Intermediates
- Deterioration or contamination-free containers should be considered for intermediates or APIs.
- Containers should be cleaned, sanitized, non-reactive, non-additive, and non-absorptive which can alter the quality of the material beyond acceptable limits.
- Containers can be re-used upon cleaning and removing previous labels as per documented procedures.
Label Issuance and Control
- Labels should be stored in a restricted area to prevent unauthorized usage.
- Reconciliation procedures should be in place for accounting labels issued, used, returned, and remained.
- Label discrepancies should be investigated and approved by the quality unit.
- Excess labels bearing batch numbers or other batch-related information should be destroyed. Also, outdated labels should also be destroyed.
- Returned labels should be segregated and identifiable to prevent mix-ups.
- Printing devices should be confirmed to the actual batch required details being printed on the label.
- Results of label printing verification should be documented and should be as per the master production record.
- A representative printed label should be affixed to BMR / BPR
Storage and Distribution
- All materials should be stored under appropriate conditions such as temperature and relative humidity to avoid contamination.
- Records for such parameters should be maintained for traceability during investigations.
- Unless there is an alternative system to prevent the unintentional or unauthorized use of quarantined, rejected, returned, or recalled materials, separate storage areas should be assigned for their temporary storage until the decision is made as to their future use.
- Quality approval is necessary to release the distribution of APIs and Intermediates
- Transportation activities should be carried out such that they don’t alter the quality of the material under scope.
- Transporting storage requirements should be available and followed by contractors.
- Distribution of the batches should be flawless to recall the batches as soon as possible.
- Following documents should be considered in overall validation policy and strategy by companies manufacturing intermediates or APIs;
- Validation Approach and Intent
- Analytical Method and Validation
- Process Control test procedures
- Computer System Validation
- Personnel responsibilities
- Critical attributes of API should be identified during the development stage or from past data. This includes critical product attributes, process parameters affecting critical quality attributes, and the expected range of these critical process parameters during commercial manufacturing.
- A validation protocol document should be written to specify the flow of process validation and how it should be conducted. This protocol should be reviewed and approved by the quality unit or respective authorized department (s).
- This validation protocol should specify the type of validation approach to be conducted e.g. Prospective, Retrospective, or Concurrent. Also, the protocol should include critical process steps and acceptance criteria.
- Upon execution, a validation report should be prepared to address the challenges performed as per validation protocol with a summary of obtained results, deviations, and corrective actions.
- Prior to proceeding for process validation, qualification of equipment and its ancillary systems should be completed including Design Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ)
- Design Qualification (DQ): Documented objective evidence that the proposed design of the facilities, equipment, and its ancillary systems is suitable for the intended use.
- Installation Qualification (IQ): Documented objective evidence that the equipment and its ancillary systems, comply with the approved design, manufacturer’s recommendations, and User Requirement Specifications (URS).
- Operational Qualification (OQ): Objective documented evidence that the equipment and its ancillary systems, perform as intended throughout the required operating range.
- Performance Qualification (PQ): Objective documented evidence that the equipment and its ancillary systems together can perform effectively and reproducibly based on the approved process specifications.
- Process Validation is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.
- Three approaches exist for validation Prospective, Retrospective, and Concurrent validation. Out of these Prospective Validation is mostly preferred with some exceptions where other approaches can be used.
- Prospective Validation should be performed on an API process and should be completed before commercial distribution of the final drug product manufactured from that API. This validation should normally be performed for all API processes in which those operations determined to be critical to the quality and purity of an API.
- Retrospective Validation can be performed for well-established processes that have been used without significant changes in raw materials, equipment, facilities, systems, or process. Also when in-process acceptance criteria and impurity profiles are readily available, retrospective validation can be considered as an approach. The number of batches selected for this validation should be sufficient and representative of all batches made during the review period including failed batches to validate process consistency.
- Concurrent Validation can be conducted when data from replicate batches is unavailable due to limited numbers or in frequency. Prior to completion of this validation, batched can be released and used in the final drug product for commercial distribution based on systematic observing and testing of the API batches.
- Number of runs for validation should be defined based on complication or magnitude of process or its modification. For prospective and concurrent validation, three consecutive successful production batches should be considered as direction. However, there may be situations where additional runs are necessary to prove process consistency. For retrospective validation, data from generally ten to thirty consecutive batches should be assessed and examine process consistency. Fewer batches can be considered provided if justifiable.
- Identified critical process parameters should be monitored and controlled while performing process validation activities.
- Process parameters that do not relate to quality such as variables controlled for energy optimization need not be included in process validation.
- Process validation should confirm that the impurity profile for each API is within the specified limits.
Periodic Validation Assessment
- Systems and processes should be evaluated periodically to verify and ensure that they are still performing in the validated state.
- Revalidation need not be performed where no significant changes have been made to the system or process when review confirms that system or process consistently producing the material meeting its predetermined specifications.
- For processes or situations where the possibility of contamination or carry-over persists which has the potential to affect the quality of API, cleaning validation should be engaged.
- If different intermediates or APIs are to be manufactured in the same equipment and with the same cleaning process, a representative intermediate or API can be selected for cleaning validation.
- Solubility and difficulty for cleaning and the residue limit calculations based on potency, toxicity, and stability should be considered.
- Cleaning validation should have a protocol describing the scope of equipment, procedures, materials, monitoring parameters, acceptable cleaning levels, and methods.
- Protocol should also indicate the type of samples to be obtained, collection and labeling methods.
- The sampling process should include rinse, swab, or direct extraction as appropriate. This should be done to detect soluble and insoluble residues.
- Swab sampling may seem impractical when product contact surfaces are not easily accessible due to equipment design or process limitations such as inner surfaces of pipes, small ports, etc.
- Analytical methods profound in detecting residues or contaminants should be validated and considered for established acceptance limits of the residue or contaminant.
- Cleaning procedures should be monitored at appropriate intervals post validation to ensure effectiveness. Visual examination can allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling and/or analysis.
- All analytical methods should be validated apart from those included in relevant pharmacopeia or other standard references.
- The degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API process.
- Qualification of the analyzing equipment should be completed prior to starting method validation.
- All records should be kept and maintained including the documentation related to the justification providing the need for the validation.
- For performing any change and its potential impact on production and quality of intermediates or APIs, a change control system should be established for evaluation.
- Documentation system should be developed for identification, review, and approval of changes related to raw materials, analytical methods, equipment, supporting systems, process, labeling and packaging material, computer systems, and specifications.
- Changes can be classified as major or minor depending on the nature and extent of those changes and also the effects of those changes process or product.
- Validation requirements including testing activities should be part of the justification for such changes.
- All documents related to the implementation of changes should be revised as appropriate.
- Once the changes are implemented, evaluation of the initial batches and testing should be performed including expiry and retest dates.
- A stability monitoring program if necessary should capture the samples produced as a result of such changes.
Material Rejection and Re-issuance
- Intermediates or APIs which fail to meet the predetermined specifications should be identified and quarantined as such. Further, they can be reprocessed or reworked as necessary. The final disposition of such materials should be recorded.
- Reprocessing generally acceptable: Putting back the intermediates or APIs (which do not conform to the required specifications) into the process and performing necessary operations as per the established manufacturing process. Also capturing all these actions into the regular manufacturing process.
- Reworking: Investigating the reasons for non-conformance should be performed prior to making decisions for the reworking of batches that do not meet the established standards. Also once the reworking is complete, documentation should demonstrate that the reworked product is of the same equivalent quality as of regular batch. The Concurrent Validation approach should be considered as appropriate for the rework process.
Solvent and Material Retrieval
- Recovery of materials including solvents should be considered acceptable provided that approved procedures exist for recovery and recovered material meet the specifications suitable for their intended application.
- Fresh and recovered solvents can be combined if adequate testing shows the suitability for all manufacturing processes in which they may be consumed.
- Materials identified as a returning one, they should be quarantined
Complaints and Recalls
- All quality-related complaints received either orally or in writing should be recorded and investigated as per the established documented procedure.
- Recording the following details should be considered:
- Name and address of the complainant
- Name and contact number of the person submitting the complaint
- Nature of complaint (Name and batch number of API)
- Date of complaint
- The initial action is taken and identification of follow-up actions
- Response provided to the originator of the complaint
- A final decision on the complained batch
- Documented procedure considering the situation for recall of intermediate or API should be established.
- In the event of a serious or potentially life-threatening situation, local, national, and or international authorities should be informed and their advice sought.
- Appropriate Good Manufacturing Practices should be applied in the production of APIs for use in clinical trials with a suitable mechanism of approval of each batch.
- A quality unit free from production should be established for approval or rejection of each batch of API for using it in clinical trials.
- Quality measures should include a system for testing of raw materials, packaging materials, intermediates and APIs.
- Labelling for APIs intended for use in clinical trials should be appropriately controlled and should identify the material as being for investigational purposes.
Equipment and Facilities
- Procedures should be in place to ensure that equipment is calibrated, clean, and suitable for its intended use.
- Contamination and Cross-contamination free methods should be incorporated for material handling practices.
Raw Material Controls
- Raw materials should be evaluated by testing or for hazardous materials, COA from suppliers should suffice.
- Production of APIs for use in clinical trials should be documented in lab notebooks or batch records as appropriate.
- Expected yields can be more variable and less defined than the commercial processes. Therefore, investigations into yield variations are not expected.
- It is normally inappropriate to conduct a process validation for the production of APIs used in clinical trials, where the single batch produced or process changes during development make batch replication difficult. Controls including calibration, equipment qualification assures API quality during this development phase.
- Process validation for commercial use should be carried out as per the Validation approach described in this guide earlier including small-scale or pilot batches.
- Every change should be properly recorded in production, specifications or test procedures.
- While analytical methods performed that may not yet be validated, to evaluate a batch of API for clinical trials, they should be scientifically sound.
- The system should be in place for retaining reserve samples of all batches ensuring sufficient quantity post-approval, termination, or discontinuation of an application.
- For existing APIs in clinical trials, expiry date, and retest date apply as described in this guide earlier. While, for new APIs, these dates normally do not apply in the early stages of clinical trials.
- Development and implementation of the analytical methods used to support the release of API batch for use in clinical trials should be documented appropriately.
- The system for retaining and controlling manufacturing records should consider the length of time post-approval, termination, or discontinuation of an application.
- Good Documentation Practices should be followed to ensure keeping records and traceability.
Agents, Traders, Distributors and Packers
- All agents, brokers, traders, distributors, packers, or labelers should comply with Good Manufacturing Practices as defined in this guide.
- All of the mentioned above should maintain complete traceability of APIs and intermediates they distribute.
- Following documents should be retained and available at their-self include:
- Original manufacturer identity
- Address of original manufacturer
- Purchase Orders
- Transportation documentation
- Receipt documentation
- Name of API or intermediate
- Batch number given by the manufacturer
- All authentic COAs
- Retest and expiry dates
- All of the mentioned above should establish, document, and implement an effective system to maintain quality as specified in this guide earlier.
Following aspects should be taken into consideration by all of the mentioned personnel
- Proper environmental conditions for Repackaging, relabelling, and holding of APIs and intermediates
- Stability studies to justify assigned expiration and retest dates of APIs or intermediates
- Transfer of information received from manufacturer to customer and vice-versa
- Handling of complaints, recalls and returns as specified in this guide earlier
Guidelines for API manufacturing by Fermentation / Cell Culture
- This section is applicable to intermediates or APIs manufactured by cell culture or fermentation using natural or recombinant organisms which are not adequately covered in other sections. However, principles of good manufacturing practices in other sections of this guide apply.
- Generally, the degree of control for biotechnological processes used to produce proteins and polypeptides is greater than that for classical fermentation processes.
- The biotechnological process refers to the use of cells or organisms that have been generated by recombinant DNA or other technology to produce APIs.
- Classical fermentation refers to processes that use micro-organisms modified by conventional methods to produce APIs. APIs from this method generally have low molecular weights.
- Two basic categories of APIs include higher molecular weight (proteins, polypeptides, etc.) and lower molecular weight (amino acids, antibiotics, vitamins).
- Cell culture or fermentation includes cell cultivation, extraction, and purification of required material from living organisms. Raw materials such as media, buffer, etc. may provide the potential for contamination growth too. Therefore, bioburden, viral contamination, and endotoxins control during manufacturing at appropriate stages may be required.
- Suitable equipment and environmental conditions should be used in a controlled manner to minimize the risk of contamination. Also, the acceptance criteria for such things should be considered depending on production steps and conditions.
- Removal of media constituents, host cells, other impurities, and contaminants should be confirmed as appropriate.
- Following process controls should be considered in general:
- Critical operating parameters during cell culture or fermentation
- Monitoring cell growth process and viability and productivity as appropriate
- Maintaining working cell bank
- Harvesting and purification procedures that remove cellular debris and media components protecting the focused product from contaminants and quality loss
- Monitoring bioburden and wherever required, endotoxins at suitable stages of production
- Safety concerns considered as per ICH Q5A, Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin
Maintaining Working Cell Bank and Records
- Storage conditions should be designed to maintain viability and prevent contamination. Cell banks should be maintained under such storage conditions. Also, records should be maintained to keep them for the use of vials from the cell banks.
- Cell banks should be periodically monitored to determine the suitability for use.
- For detailed guidelines on cell banking, refer to ICH Q5D, Quality of Biotechnological Products: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products.
Cell Culture / Fermentation
- For aseptic additions, closed contained systems should be used wherever possible to minimize the risk of contamination.
- Manipulations using open vessels should be performed in biosafety cabinets or controlled environments wherever the quality of API can be affected by contamination.
- Proper personnel gowning procedures and special precautions should be practiced while handling the cultures.
- Critical operating parameters should be monitored to ensure proper process control such as temperature, pH, agitation rates, additions, pressure, etc.
- Cell growth, viability, and productivity should be monitored as appropriate. For example, viability may not be monitored for classical fermentation.
- Post batch cleaning and sterilization activities should be carried out to protect the quality of API.
- Procedures for identifying and eradicating contamination should be in place including impact assessment and corrective actions. Additionally, contaminations should be logged and recorded.
Harvesting, Isolation and Purification
- Harvesting steps, either to remove cells or cellular components or to collect the cellular components after disruption, should be performed in equipment and areas designed to minimize the risk of contamination.
- Harvesting and purification procedures should be adequate to ensure that the intermediate or API is recovered with consistent quality.
- For open systems, purification should be performed under appropriate environmental conditions to preserve product quality.
Viral Removal or Inactivation Steps
- These are critical processing steps for some of the processes and should be performed within their validated parameters.
- Appropriate measures should be taken to prevent potential viral contamination from pre-viral or post-viral removal/inactivation steps.
- Open processing should be performed in separate areas than other processes with dedicated Air Handling Units.
- For more specific information on this section, refer to ICH Q5A, Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin.
ICH Q7 has laid down the guidelines for good manufacturing practices considering a panorama of pharmaceutical-related sectors along with the simple yet important classification of the different areas of the facility.
It is the manufacturer’s responsibility to ensure they stick to good manufacturing practices guidance and consider their facility accordingly.
This article was aimed to provide you key points of every heading covered under the mentioned guideline. Proper interpretations and applicability of the required facility are dependent on the type of facility that’ll manufacture the APIs.