Goals
When you have completed this module, you should be able to:
Ø Perform an audit of an API manufacturer
Ø Use a range of tools and information, including the contents of this module and the Internet, in support of auditing an API module
Ø Understand and apply applicable GMP standards to an audit of an API manufacturer
Ø Recognize compliance or non-compliance of API manufacturers to applicable regulations
Definitions
Active Pharmaceutical Ingredient (API): Any substance or mixture of substances intended to be used in the manufacture of a drug medicinal product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effecØt in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.
API starting material: A raw material, intermediate, or an API that is used in the production of an API, which is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a materials purchased from one or more suppliers under contract of commercial agreements, or produced in-house.
API packaging material: Any material intended for protect an intermediate or API during storage and transport.
Batch Production record: The document used for each individual batch of API, based on the master production instruction.
Blending: The process of combining materials, each within the same specification, to produce a homogeneous intermediate or API.
Centrifugation: A method of separating a solid/liquid mixture by rotating it at high speed in a cylindrical container. The solid will remain on the sides (through centrifugal force) while the liquid goes to drain.
Critical: A process step, process condition, test requirement or any other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification.
Critical Process Parameters: A process step, process condition, or any other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification. The requirements or specifications of an API or API process that can be measured and controlled to produce the desired quality of the API.
Critical Quality Attributes: A characteristic of the API that contributes to its quality and is evaluated in terms of whether it does or does not exist, with respect to a given requirement.
Crystallization: The formation of pure to nearly pure crystals of small or big molecules. Often used to purify a substance; crystallization of proteins is used to obtain their three- dimensional structure by x-ray analysis.
Deviation: Departure from an approved instruction or established standard.
Distillation: A process in which liquid is boiled, vaporized and condensed to increase purity.
Endotoxin test: A test designed to determine if there are endotoxins in the API/drug product. Endotoxins are toxic molecules consisting of lipopolysaccharide originating from the outer cell wall of Gram-negative bacteria. Endotoxins may cause a fever reaction in humans.
Expected yield: The quantity of material or the percentage of theoretical yield anticipated at any appropriate phase of production based on previous laboratory, pilot scale or manufacturing data.
Extraction: The removal of a chemical from a mixture by the use of a selective solvent.
Fermentation: A process in which an agent such as yeast, a bacterium, mold or enzyme causes an organic substance to break down into simpler substances.
Filtration: The separation of a solid from a fluid by passing the liquid through a filter, cloth, or other porous medium.
Filtration: The separation of a solid from a fluid by passing the liquid through a filter, cloth, or other porous medium.
Heel: An expression used for build-up of material in equipment used for continous or campaign production leading to a risk of carry-over of contaminants (e.g. impurities or microorganisms). Examples of risks for significant carry-over between batches are filtration and micronisation.
Impurity: Any component present in the intermediate or API that is not the desired entity.
Impurity profile: A description of the identified and unidentified impurities present in an API.
Master production instruction: The approved process document or “recipe” that is used for preparing every batch of the intermediate and API.
Mother liquor: The residual liquid that remains after the crystallization or isolation processes. A mother liquor may contain materials that did not react, intermediates, levels of the API, and/or impurities. It can be used for further processing.
Parenteral: A pharmaceutical term used to describe a drug product that is sterile and delivered through injection/infusion.
Pyrogen: A substance that can produce a fever in an animal system.
Quarantine: Isolating materials either physically or by other means pending a decision on their subsequent approval or rejection.
Reprocessing: Taking the same material and repeating steps that are already part of the normal process.
Reworking: Taking already manufactured material and performing steps that are not part of the normal process
Seed material: A small amount of material used to start a chemical reaction, typically an approved lot of the material containing the desired crystal form which is added to start a crystallization process.
Stability-indicating assay: A validated quantitative analytical procedure that can detect the changes with time in the pertinent properties of the drug substance and drug product.
Explanation of Topic
GMP and Active Pharmaceutical Ingredients (APIs)
An active pharmaceutical ingredient or API is the therapeutic material found in a drug product. It can be derived from a chemical or biological sources. Along with excipients it is the starting or raw material for a drug product. It is also defined as a drug substance in the ICH Q7A guidance- Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients. This GMP guide is a truly harmonized guide developed through the ICH process involving both industry and regulators across the world. The guide is implemented in most parts of the world.
Differences between manufacturing a drug product and an API
APIs are produced by processes different from drug product processes. Some of these processes are chemical or enzymatic reactions, recombinant DNA technology, cell culture/fermentation, recovery from natural materials, or a combination of processes. API processes are characterized by transforming the starting material and intermediates through a number (e.g. as few as 2-3 for simple chemical synthesis to 100’ of steps for peptides) of process stages before purification and isolation. The importance of the process step to the critical quality attributes of the API usually increases as one approaches the final API stages, although some earlier steps may be key to API quality. The manufacturer should have a good scientific understanding of the purpose and criticality of each process step.
Differences in API Facilities
API facilities may range from large vessels of 1000’s of liters for chemical synthesis or fermentation to small scale laboratory glassware. Some equipment may be located outdoors but must provide adequate protection to the material. Controls are most critical when API systems are open. Controls for APIs that could be sensitizing, toxic, or require microbial control will be different. Level of control may be different for final dosage due to quantities and concentrations of materials.
GMP in Relation to API operations
GMP is applied in the receipt of materials, production, packaging and repacking, labeling and relabelling, quality control and release, storage and distribution. The GMP level increases throughout the production process from starting materials through intermediates to API and it is important for the manufacturer to define where GMP starts. Table 1 in Q7A gives guidance in application of GMP.
In a cell culture/fermentation process, Q7A applies to the following:
* Maintaining the working cell bank
* Cell culture and/or fermentation
* Isolation and fermentation
* Physical processing and packaging
GMP is to be applied to the manufacture of APIs for use in Medicinal Products. If the API is to be used to manufacturing a non-sterile Medicinal Product, Q7A applies to the following:
* Introduction of API starting material
* Production of intermediates
* Isolation and purification
* Physical processing and packaging
If the API is to be used in a manufacturing process for a sterile product but does not need to be sterile in itself additional requirements need to be considered such as quality of water used and type of facilities used for the final steps If the API is required to be sterile to be used in an aseptic manufacturing process, this training module will only cover the API process up to the point where the product is becoming sterile (e.g. filtration with a sterilizing filter).
GMPs should increase in the level of sophistication and documentation as an API process nears production of the final API. This includes more detail in batch record, level of sophistication of analytical methodology, and level of protection from contamination with more stringent environmental controls.
What is an API audit?
An API audit is an audit of the buyer site to the suppliers.
The goal of an API audit should be to verify that the sites comply with the principles of GMP for APIs. In order to certify/qualify deliveries the manufacturing and testing facilities used by the manufacturer need to be audited in order to evaluate possibilities for accepting material based on Certificates of Analyses rather than performing full in-house testing. API audits are part of the certification program and should be performed regularly according to an approved schedule. Providing high quality chemicals to pharmaceutical dosage form manufacturers is of critical importance in safeguarding the health and well being of our patients. This training unit will outline the requirements and steps to follow in the performance of QA Audits of API processing operations. To see how GMP is applied, it is important to understand the API process.
General Overview of API Manufacturing
Manufacturing process for Chemical APIs
The chemical synthesis process begins when raw materials and solvents are brought together and charged into vessels (reactors) with a subsequent chemical reaction. Typical chemical reactions in API manufacturing include Grignard reactions (addition of a reagent to a keton or aldehyde to form a secondary or tertiary alcohol), hydrolysis, halogenation, hydrogenation and oxidations. Frequently, a catalyst is added to the raw materials to initiate a chemical reaction. The catalyst will not be consumed during the chemical reaction. Multiple chemical reactions typically occur to form the “raw” API active molecule. This molecule is not pure and must undergo purification to eliminate process impurities, which may include unreacted raw materials, residual solvents, degradation products, by-products, etc.
The purification may include:
* Distillation
* Extraction
* Filtration
The final molecule is usually in liquid form and has to be isolated through crystallization. Crystallization may be achieved by cooling the reaction mixture or adding a solvent, which causes solid crystals to form within the liquid.
This results in a mixture called a slurry. Often, the crystallization may be induced by a seed material. The seed material’s role is to induce the desired crystal form of the API.
A centrifuge filter pad is used to separate crystals, also known as a “cake” of crystals, from the liquid and then discharge the mother liquor. A mother liquor may contain unreacted materials, intermediates, levels of the API and/or impurities Recovery (e.g. from the mother liquor or filtrates) of reactants, intermediates, of the API is considered acceptable, provided that approved procedures exist for the recovery.
The recovered materials must meet specifications suitable for their intended use. Once the API has undergone one or more of the above steps, centrifugation or pressure filter may be used to separate the solid (API) from the solvent (fluid).
The isolation of the API solid is followed by a drying process. Depending on the finished API particle size requirement and the finished dosage formulation process, a milling step may be required. The regulatory authorities considered milling as part of the pharmaceutical manufacturing process in many countries, particularly if the particle size is of importance in the finished dosage form. The finished API is then packaged and transferred for manufacturing of a finished dosage form.
Important elements of the Quality System
GMP for API manufacturing contains most elements found also in the GMP for finished product dosage forms. Some elements may differ and there are also additional elements to be aware of.
Below some of the GMP elements are mentioned briefly and references are made to other training. It should be noted that for API for use in clinical trials not all GMP controls for manufacturing are appropriate during the development of the new API. Specific guidance is given in section 19 of ICH Q7A.
Quality Management
To ensure that the product meets quality specifications, the API manufacturer must have an established quality unit.
The responsibilities of the Quality Unit cannot be delegated. They include releasing or rejecting:
* All APIs,
* Intermediates for use outside the control of the manufacturing company,
* Raw materials,
* Packaging materials, and Labels.
In addition they need to review completed production and lab records of critical process steps and perform product quality reviews.
The Quality Unit must also approve specifications and master production instructions, all procedures impacting on quality, contract manufacturers, changes that potentially impact quality, and validation protocols and reports. The Quality Unit also has the responsibility to ensure that:
* Critical deviations are investigated
* Internal audits are performed
* Process changes are evaluated and approved
* Facilities are maintained in a good state of repair
* Effective systems exist for qualification, calibration, control and maintenance of critical equipment
* Utilities (e.g. water, compressed gases) are qualified and monitored
* Effective systems exist for calibration of critical equipment
* Materials are properly controlled per their status, tested and results reported
* Product release. Note that regulations do not require a QP release of APIs.
* Annual product quality reviews are performed
* Stability data exists to support retest or expiration periods
* Rework/reprocessing is controlled
Personnel
Qualified personnel must be available to perform and supervise the manufacture, processing, packing, holding, and testing of APIs.
A special dress code should be in place for controlled areas. The site should have a written approved SOP describing the dress code.
Buildings and Facilities
Buildings and facilities must be of suitable size, construction, environment, and designed to minimize contamination and cross-contamination of APIs. ICH Q7A requires dedicated production areas for production of highly sensitizing material such as penicillins or cephalosporins. This should include separate air handling systems for the isolation and packaging of these materials.
Constructions that ensure containment are beneficial with regards to minimizing cross contamination/contamination risks. Furthermore ICH Q7A says that dedicated production areas should also be considered when material of an infectious nature or high pharmacological activity or toxicity is involved e.g. certain steroids or cytotoxics unless validated inactivation and/or cleaning procedures are established and maintained.
The current position of many sites is that penicillins must be produced in dedicated facilities. For the other products a risk assessment of the potential for cross contamination from multi product facilities should be undertaken, taking into account factors such as the potency, cleanability, containment technology and facilities / equipment used.
Many API plants are predominantly closed systems and focus should be given to points of materials addition, or product removal / isolation, when the system is open to the environment.
Utilities
The rationale for appropriate water quality for each process should be documented. Potable water is the minimum water quality but the water quality depends on the stage of its use in the manufacturing process, intended route of administration for the finished product and the nature of the API. If a non-sterile API will be used to prepare a sterile drug product, the water used for the final isolation and purification steps of the API may be purified water.
This purified water needs to be monitored for specific micro- organisms, the endotoxin level and the total microbial count. If a non-sterile API will only be used for a non-sterile drug product, purified water may be used and only needs to meet the requirements for purified water. If the use of the API is not known the more stringent criteria should be applied.
Air systems should be designed to prevent contamination and cross-contamination. If appropriate, air filtration, dust collection, and exhaust systems should be used in production and packaging areas where the product may be exposed. Air handling units for dry processing areas (i.e. drying, milling and packaging areas) should be independent. Pressure differentials should exist and be monitored.
Gases coming in contact with an API (e.g. steam, nitrogen) must comply with the appropriate specifications to ensure they do not alter the API quality. The generation and distribution systems for gases coming in contact with an API must be qualified and routinely monitored to ensure it is of suitable quality and free of contaminants.
Process Equipment
Major equipment and permanently installed processing lines should be identified. Defective/obsolete equipment should be appropriately tagged and removed from service.
Equipment should be designed to minimize the risk of microbial or particulate contamination. Equipment should be qualified within the operating range and/or across overall operating capability since the equipment may be used for different products. Instruments used for critical measurements should be appropriate for their use and calibrated at specific intervals.
This includes, but is not limited to, temperature indicators, pressure gauges, pH probes and scales. Where appropriate such data should be part of the batch record and reviewed.
Cleaning
Cleaning procedures for equipment should be validated to prevent contamination from residual chemicals. As the stringency of GMP in API manufacturing should increase from early API steps to final steps also for cleaning the stringency and validation requirements should increase from early steps to final steps reflecting the risk to the quality of the API and subsequent drug product.
The specifics of API manufacturing (multi step processing, chemical reactions, complex plant and equipment with difficult access) mean that specific guidance is required to ensure effective cleaning and validation. To ensure API plants can be effectively cleaned it is necessary to actively plan for cleaning during the plant/equipment design.
Trial cleaning can be used to collect data for a specific cleaning procedure and to identify spots, which are difficult to clean. The results of trial cleaning should be evaluated to help establish optimal cleaning procedures. The justification for any cleaning approach should be based upon an understanding of the impact it will have.
If campaign manufacturing is performed this should be included in the validation. A new accommodation of a product into an existing plant should take account of the attributes of the product and the capability and design of the plant with respect to cleaning. Performance of cleaning processes must be documented. Status of cleaning and maintenance should be recorded and checked, (e.g. a logbook or cleaning record). The need for cleaning should also be considered for transfer of APIs or intermediates between reactors.
Documentation and Records
Any production, control or distribution record specifically associated with a batch of API should be retained as required by the regulations. These documents may be retained in paper or electronic form. Written procedures should be established and followed for investigating unexplained discrepancies and include results out of the expected yield range, batch failure to meet specification and out of specification results. An annual product quality review should be performed on a representative number of batches and their associated records, which include process changes, stability data, complaints, recalls, returned APIs and deviation investigations.
Materials Management
The criticality of each raw material to the API process and its key quality attributes must be understood and factored into the controls applied to it. Raw materials should only be sourced from formally approved suppliers. This should include an evaluation, which provides adequate evidence that the manufacturer can consistently provide product meeting all specification clauses.
As a minimum one test should be completed on receipt to confirm the identity of the material. Full analytical testing of receipted materials can be reduced once confidence in a supplier has been established but only after a minimum of three separate conforming batches/deliveries have been received and tested. Raw materials (including those received in tank trucks) and packaging materials should be received, sampled, tested, approved and stored. Materials received in tank trucks should also be quarantined, tested and released prior to loading them into the tank farm. Non-dedicated tankers should be accompanied by a cleaning certificate for each supply.
Large storage tanks or silos in the tank farm should be identified and their contents periodically tested to assure no deterioration occurs. Packaging and labeling materials should also be sampled, tested, and released for use based on established specifications. Labels should be stored in a secure location, with limited access. Printed labels should be reconciled.
Validation and Production Controls
For API processes, validation is required for critical steps, which need to be defined during development. The steps of the synthesis requiring formal validation should be identified. Validation should ensure that the manufacturing process has the capability to produce a consistent product in a reliable manner. Validation should include API steps that are critical to the quality and purity of the final API product. Process validation defines the API in terms of Critical Quality Attributes.
Critical Quality Attributes (CQA) may include:
Ø Chemical purity
Ø Impurity profiles
Ø Particle size
Ø Density
Ø Moisture and solvent content
Ø Homogeneity
Ø Microbial quality
Critical Process Parameters that affect Critical Quality Attributes must also be identified and ranges established. Different API processes may have different critical process parameters.
Typical Critical Process Parameters are:
Ø pH
Ø Pressure
Ø Temperature
Ø Mixing speed
These critical process parameters should be routinely recorded with specified ranges during the manufacturing stages and verified as acceptable at batch release. Time limits for the completion of significant manufacturing steps should be established and documented.
For intermediates that are isolated and stored before further processing, storage conditions, hold times and container types must be specified.
For APIs process changes assurance should be gained that there is no impact upon the impurity profile and/or other key API quality attributes. Packaging and Labeling should be performed according to written procedures. Printing devices should be monitored to ensure that all imprinting conforms to established specifications. Where intermediates and APIs are intended to be transferred outside the control of the manufacturer’s material management system, retest/expiration dates must be on the label.
The label should contain special shipping or storage conditions for an API or intermediate. Packaging and labeling facilities should be inspected prior to use, as a precaution for mislabeling. This should be documented.
APIs shipped outside of the manufacturer’s control must have tamper evident seals attached/securing the container. A system must exist to ensure that the distribution of each lot can be determined in order to facilitate recall procedures.
Storage and Distribution
If agents, brokers, traders, distributors, repackers or relabellers are used it needs to be ensured that they comply with GMP as described in Q7A including maintaining traceability.
It is the responsibility on the manufacturer to ensure that the shipping contractor knows and follows appropriate conditions.
Laboratory Controls
GMP requirements for API laboratories are the same as the laboratory requirements for finished dose drug products. Laboratory reagent “use by” dates should be determined using experience and sound scientific judgment and do not require formal stability programs.
The impurity profile of an API should be compared, at appropriate intervals, to the profiles submitted in the regulatory submission or to historical data to detect changes resulting from modifications in raw materials, equipment operating parameters or the production process.
The degree of validation of analytical methods should reflect the purpose of the analysis and the stage of the API process. Validation of methods may not be required for raw materials, solvents, packaging materials. Validation is required for API’s and critical intermediates.
The degree of validation of in-process methods depends on the criticality and purpose of the test. Appropriately identified reserve samples of each API batch should be retained for at least one (1) year after the expiry date of the batch assigned by the manufacturer, or for three (3) years after distribution of the batch, whichever is longer.
The reserve samples should be stored in the same packaging system in which the API is stored. Sufficient quantities should be retained to permit analyzing should the need arise.
Certificate of Analysis
The certificate of analysis should contain information about the API or intermediate as shown below. The Certificate of Analysis should be complete, signed and dated by a Quality Unit representative.
Figure: Certificate of Analysis
Stability Monitoring of APIs
An ongoing, documented stability program should be established to monitor the stability characteristics of APIs. The results should be used to confirm appropriate storage conditions and retest or expiration dates. Test procedures should be validated and stability indicating. Stability samples should be stored in containers that simulate the market container (see ICH Q7A for a description of a stability monitoring program). An API expiration or retest date should be based on evaluation of data derived from stability studies. Common practice is to use retest dates, not an expiration date.
Expiration and Retest Dating for Intermediates
Supporting stability information should be available to support expiration/retest dates assigned to intermediates intended to be transferred outside the manufacturer’s material management system. Intermediates are not required to be monitored for stability on an ongoing basis.
Rejection, Reuse of Solvents, and Reprocessing/Rework
Intermediates and APIs that fail established specifications should be identified as “failed” and quarantined. These intermediates or APIs may be reprocessed or reworked. Reprocessing is repeating a processing step that is part of the established manufacturing process.
Reprocessing can be performed with approval from the Quality Unit on conforming batches or non-conforming batches to further purify them or to better meet specifications (e.g. re-milling to different specifications, repeating drying or re- crystallization).
Any reprocessing should be documented. The need for frequent reprocessing should be investigated and depending upon its root cause may need to be incorporated into the routine process. Reworking is introducing non-conforming batches into a processing step that is different from the established process (e.g. crystallization with a different solvent).
Reworking is not normally undertaken and requires QA approval. A method for rework must be included in the regulatory filing. Validation of the rework may be concurrent since typically the manufacturer will not have multiple batches. One batch with an interim report is acceptable, with the concurrent validation completed following manufacture of three successful rework batches.
If solvents are reused in a manufacturing process, the solvent recovery operations should be controlled and monitored. Typically solvents are recovered and reused in the same process. Recovered solvent may require different specifications than fresh solvents such as absence of process related impurities. Recovered solvents must be tested to demonstrate that the solvent meets pre-determined specifications, which are typically similar to the specifications for fresh solvent. The testing should also demonstrate the removal of process impurities.
If recovered solvents are re-used in the manufacturing process, there should be adequate documentation regarding both recovery method and testing results and confirmation of no adverse impact on the API quality.
Blending Batches of Intermediates or APIs
Batches of intermediates or APIs may be blended under certain conditions. Each batch that is incorporated into the blend should have been manufactured using an established process and should have been individually tested and found to meet appropriate specifications prior to blending. Out-of specification batches should not be blended with other batches for the purpose of meeting specifications.
Blending may be performed for the following reasons, but is not limited to them:
* Blending small batches to increase batch size
* Blending of tailings (i.e. relatively small quantities of isolated material) from batches of the same intermediate or API to form a single batch
All blending processes should be adequately controlled and documented. Each blended batch should be tested for conformance to established specifications. The batch record should include enough information to be able to trace back to the individual batches used in the blending. If APIs are intended for use in solid oral dose forms or suspensions where physical attributes are critical, the blending operations should be validated to show the homogeneity of the combined batch.
Critical attributes (e.g. particle size, distribution, bulk density and tap density) should be tested during validation since they may be affected by the blending process. It needs to be demonstrated that there is no unacceptable build-up of impurities or microbial contamination during continuous or campaign production due to residuals left between batches/lots (heels).
This includes considerations of cleaning regimes, minimizing the amount being carried over, stability to repeat operations as well as batch dating. The risk of carry-over of contaminants can be controlled through established cleaning intervals. Examples of risks where significant carry-over can occur between batches are filtration and micronisation.
Certificates of Suitability
Manufacturers of APIs may be holders of certificates of suitability issued by the European Directorate for the Quality of Medicines, EDQM. Under this official procedure, manufacturers or suppliers of substances for pharmaceutical use can apply for a certificate concerning: the evaluation of the suitability of the monograph for the control of the chemical purity and microbiological quality of their substance according to the corresponding specific monograph, or the evaluation of reduction of Transmissible Spongiform Encephalopathy (TSE) risk, according to the new general monograph, or both.
This procedure is aimed at facilitating and simplifying exchanges between the partners to ensure that the quality of substances is guaranteed and that these substances comply with the European Pharmacopoeia. Certificate including revoked certificates are listed at the EDQM website. Some but not all of the certificate holders have been inspected by EDQM.
Summary
The production of APIs must be a controlled process. As the process moves closer to producing the final API, GMPs will become more important. Depending on what the API will be used for, the level of GMP compliance will increase.
Key Parameters in Conducting an API Audit
Prior to the audit
Ø Determine which APIs the supplier manufactures for the site.
Ø Determine how the APIs will be used and in what finished drug product. If the API will be used as a direct component of a drug product, used in the preparation of a sterile drug product, or is represented by the manufacturer as being pyrogen free, this should make a difference in the audit.
Ø Try to obtain a complete list of APIs manufactured by the supplier and review it for concerns regarding risks for cross contamination Determine if the supplier is the holder of any certificates of suitability
Ø Review Quality Agreements
Ø Regulatory Authority findings
Ø Review reports/corrective actions from previous audits.
Ø Determine any issues including deviations and changes observed with the APIs received since the last audit of the supplier.
Ø Review the history of the manufacturer with the site.
Ø Review the Drug Master File (DMF).
Ø Obtain a copy of a recent Certificate of Analyses received by the site and compare with raw data at the API manufacturer.
During the audit
During the walk-through
Ø Observe the process flow and process areas and determine if there is a contamination risk for in-process materials.
Ø Observe a process in operation. Determine if:
– All items (sample scoops, bags, etc) taken into an API packaging room/area are listed in the manufacturing batch record and thatnaccountability of these items is completed.
– The batch record is concurrent with the process.
– Personnel are following the dress code.
– Intermediates and API are exposed to the environment. If so, where in the process does this take place.
Ø Confirm that all equipment is identified.
Ø Determine if the facility and processing equipment are dedicated to one product or used for numerous products.
Ø Determine if the processing equipment is an open or closed system.
Ø Ensure that controls are in place to prevent contamination.
Ø Verify that there are adequate space and environmental controls to ensure product integrity and to prevent cross-contamination or product mix-ups.
Ø Ensure that systems are in place to prevent cross contamination from the manufacturing environment, external surrounding environment, equipment, overhead utilities, or other starting materials, intermediates or APIs.
Ø Verify that the facilities and equipment are maintained in a good state of repair and cleanliness.
Ø Verify that the manufacturing environments (all production areas) are appropriately controlled for the process taking place to protect the API against deterioration and contamination.
Ø Verify that there is an adequate program to protect components from contamination from insects, rodents, birds and other vermin. Determine that the API manufacturer has an established Quality unit.
Ø Verify that the Quality unit’s authority and responsibilities are clearly defined in writing.
Ø Confirm that an internal quality audit program for all areas of operation has been established to verify that SOP’s and other procedures and policies are being followed and to determine the effectiveness of the quality systems.
Ø Verify that approved procedures exist for processing and investigating deviations, Out Of Specifications and complaints, as well as reporting complaints and tracking resolutions.
Ø Verify that there is an established, approved Quality System/Quality Policy that is endorsed by management.
Ø Verify that a system is in place to notify the buyer site if subcontractors are used and how subcontractors are qualified.
Ø Verify that a communication system is in place to notify the buyer site about 1) significant process changes prior to implementation, and 2) any stability failures that are product related.
Ø Ensure that quality does not delegate their responsibility and is responsible for assuring that:
– Internal audits are performed.
– Effective systems exist for calibration and maintenance of critical equipment.
– Materials are tested, results reported and evaluated.
– Stability data exists to support retest or expiration periods.
Ensure that personnel have received adequate training.
Ø Verify that there is a documented training and qualification program for each job classification.
Ø Verify that job-specific training is conducted and documented for each employee.
Ø Verify that training is conducted with sufficient frequency to assure that employees are familiar with current applicable regulations and are trained in process and methodology changes.
Ø Verify that there are clearly written job descriptions for all personnel.
Ø Confirm that all personnel comply with the dress code established for all areas of manufacturing as documented in a site SOP.
Ensure that process equipment is controlled and qualified.
Ø Verify that critical instrumentation is on a calibration and preventative maintenance program.
Ø Verify that process equipment has been qualified within its operating range.
Ø Verify that there is a written approved protocol/final report, which includes equipment deviations and evaluation of the deviations for impact.
Ø Verify that preventative maintenance and repairs, as well as calibration operations, are documented.
Confirm that cleaning practices are in compliance with site SOPs.
Ø Determine whether equipment is dedicated to one line or process or non-dedicated. “Equipment” refers but is not limited to (utensils, sample thieves, reactors, centrifuges, tray dryer).
– If equipment is not dedicated, ensure that it has undergone cleaning validation.
Ø Assure that analytical test methods employed during cleaning validation were validated.
Ø Assure that swab sampling and testing included swab recovery studies.
Ø Verify that acceptable residual limits were established.
Ø Ensure that there is adequate housekeeping, especially where in-process material is exposed and in the drying and packaging areas.
Ø Ensure that there is an adequate system for documenting cleaning.
Ø Verify that there is evidence that the cleaning process for non-dedicated equipment is adequate to remove previously manufactured material.
Ensure that the production process is controlled and validated.
Ø Verify that the process has been validated.
Ø Verify that there is a procedure for clearly defining the date of manufacture.
Ø Verify that there is evidence to demonstrate that the manufacturing process produces APIs that meets established specifications consistently from batch to batch.
Ø Verify that critical process parameters have been defined and are controlled.
Ø Verify that there is an adequate system, described in an SOP, for controlling process changes. The system should include:
1) maintenance of a change log
2) involvement by the quality unit in the change procedure
3) evaluation of the impact of the change on the API.
Ø Determine if the changes have been performed according to the manufacturing site’s change control procedure.
Ø Confirm that critical process parameters are established and controlled.
Ø Confirm that process parameters are appropriately documented in batch records.
Ensure that Packaging and Labelling operations have sufficient control.
Ø Protect quality and purity of the API
Ø Assurance that the correct label is applied to all containers.
Ø Designed to prevent mix-ups.
Ø Procedures to ensure that the correct quantity of labels are printed and issued and the labels contain the correct information. Excess labels should be immediately destroyed or returned to controlled storage. All excess labels bearing lot numbers should be destroyed. Packaging and labelling facilities should be inspected immediately before use to ensure that all materials that are not required for the next packaging have been removed. Direct printing should satisfy that intent.
Review an example of a rework procedure
Ø Ensure that a change request was completed for the rework procedure
Ø Ensure that the procedure outlined in the change request was followed and documented.
Ø Verify that the rework procedure is being concurrently validated.
Ø Verify that a regulatory filing was submitted for the rework procedure.
Review an example of documentation related to reprocessing of material
Ø Ensure that the manufacturing steps used match the validated process steps.
Ø Ensure that the Critical Process Parameters were met.
Ø Ensure that the appropriate release tests have been completed.
Determine that the API manufacturer has a controlled system for management of materials.
Ø Verify that raw materials, including those received in tank trucks, are checked upon receiving to assure that the:
– Material has the correct labels & compliant C of A/C of C
– The seal is intact
– The container is not damaged
Ø Verify that there are adequate written and approved instructions for raw material sampling and testing.
Ø Verify that raw materials have been assigned a retest date.
Ø Verify that the storage of material is designed to prevent contamination, cross contamination and damage.
Review documentation.
Ø Review deviations/investigations and corrective and preventative actions.
– Ensure that root causes have been identified.
– Determine if there are any trends.
Ø Determine if equipment maintenance is the root cause of process deviations.
Ø Perform a review of documentation throughout the processing areas by reviewing:
– Cleaning and use logs
– Maintenance logs
– Production batch records
Ø Ensure that there is a complaint system in place with a means to track complaints.
Ø Verify that there are complete written manufacturing instructions/batch reports that specify quantity and identity of raw materials, equipment, manufacturing flow, operating parameters, in-process sampling, packaging materials, labeling and documentation of each significant step.
Ø Verify that the supplier’s SOPs for cleaning and change over from one product to another have enough detail. Verify that there is adequate documentation to support the effectiveness of these procedures.
Ensure that there is traceability for all items included in the production of the API as well as the Finished API product.
Review the API stability program (stability chambers; packaging and control of samples and test data).
Evaluate Solvent Recovery system
Ø Ensure that recovered solvent is tested against defined specifications
Ø Ensure that recovered solvent is not added to a storage tank containing released solvent until all test results are received.
Determine that the process water used in API manufacturing is suitable for its intended use.
Ensure that APIs for sterile products have been produced under adequately controlled conditions
Ø Verify that the manufacturing environment and equipment are adequate to minimize microbiological contamination, which includes monitoring of the environment, adequate gowning of personnel and testing of process water.
Ensure that computer systems have been validated.
Ø Verify that computer systems have been demonstrated and documented to consistently function as expected, if used in the manufacturing process.
Ø Verify that there are procedures to govern change control of computerized systems or programs, including training of personnel subsequent to changes.
Ensure the Quality laboratory meets GMPs standards
Ø Verify that training and qualifications are documented for all laboratory personnel.
Ø Verify that written and approved test methods and acceptance specifications are available to the analyst for all samples to be tested.
Ø Verify that there are procedures for qualification (IQ/OQ) of new and/or modified laboratory instruments and equipment.
Ø Verify that there are established practices to insure proper storage and handling of reference standards, reagents, volumetric and test solutions, with labeling to indicate their identity, date of preparation or receipt, expiration date and other appropriate information.
Ø Verify that there are procedures for the preparation and maintenance of complete and appropriate written laboratory records.
Ø Verify that there are procedures in place for a review of laboratory records by a second chemist, supervisor and/or the Quality Unit.
Ø Verify that there is a SOP for investigation of out-of-specification (OOS) results, atypical results, and test deviations, including specific procedures for re-measurement or retesting, and a time frame for completing investigations.
Ø Determine whether all tests are performed on every batch or not and how this has been justified.
Ø Verify that tests are performed in accordance with relevant pharmacopoeias/DMF/other as appropriate.
Ø Verify that appropriate sampling procedures are in place.
Verify that the Certificate of Analysis for the API includes the following:
Ø Name (compendial/trade), grade, pharmacopoeial designations, and specific lot/batch number for the material
Ø Name of supplier, identity of the manufacturer, and manufacturing site
Ø All tests, results, and specifications for the material
Ø Date of manufacture
Ø Expiration date and/or recommended re-evaluation date
Ø Appropriate authorization (signature, title, date)
Ø Verify that there is a procedure to insure that all information on the final COA receives appropriate review, and that adequate controls are in place to prevent unauthorized changes to the COA.