Abstract
In the pharmaceutical industry, each and every activity is done according to standard operating procedures and protocols. Standard operating procedures are the pre-established stepwise instructions to carry out routine operations while protocols are predefined written document used for design and execution of experiments. In the current scenario, pharmaceutical industry wants to manufacture quality product as per good manufacturing practice guidelines. To achieve six sigma qualities, deviations are very important to consider. Deviations have to be addressed, investigated, and based on investigation data, suitable corrective actions and preventive actions are applied for prevention of its reoccurrence. Corrective actions and preventive actions are important part of quality management system. Corrective actions and preventive actions is a system which falls under good manufacturing practice and many International Standard Organization business standards. Corrective actions and preventive actions include route cause analysis for resolving deviation, which includes its cause of identification, and helps to prevent its occurrence in future. Corrective actions and preventive actions is a combination of ideas and tools to correct deviation. Inappropriate initial route cause identification and application of corrective actions and preventive actions lead to extra work, time, and cost. There are some exceptional cases in which corrective actions and preventive actions are not required, for instance one-time deviation, where only corrective actions are done. The corrective actions and preventive actions system improves and maintains processes, procedures, organization, and business in a systematic, organized, well-documented, and actionable way. In this article, case studies of deviations in pharmaceutical industry helped in identification and evaluation of deviation and based on that application, suitable corrective actions and preventive actions are shown which give thorough understanding of deviation and application of corrective actions and preventive actions in pharmaceutical industry. So, corrective actions and preventive actions are not only regulatory requirements but they make good business sense to the pharmaceutical industry.
Keywords
Introduction
In the pharmaceutical industry, deviations are important. Deviation is a departure from approved procedure or specification. A deviation is an activity performed differently and/or modified than that specified in an approved document which includes standard operating procedure (SOP), protocol, standard test procedure, batch manufacturing record (BMR), etc. When deviations are being handled it interfaces with the corrective actions and preventive actions (CAPA) system and the quality management system (QMS).1,2
Investigating quality-related issues and tracking them closure is one of the most critical activities in QMS. The increased importance of risk-based approaches is leading regulators to look for a well-defined process in investigating and identifying the root cause and the method of implementation of the CAPA plan.
Most pharma companies view CAPA as an activity intended to address identified quality issues but fails to take a holistic approach to address them. This is evident from the warning letters published by regulatory agency. Such a partial approach to CAPA results not just in rework, but also time and revenue. Successful CAPA management requires addressing quality issues efficiently and effectively. CAPA should not only correct and prevent the quality issues, but also proactively apply the approaches practiced to prospective areas where the issue might ensue.
Examples of deviations: Examples for potential deviations in different areas of pharmaceutical industry are given in Table 1, which may be minor, major, or critical deviations. 3
Examples for potential deviations in different areas.
Deviation
There are two types of deviation4,5: planned deviation and unplanned deviation.
Planned deviation: Planned deviations, which are described, and preapproved deviation from the current operational document/system, covering a specified period of time or number of batches. Planned deviation shall be approved before execution. So these are the deviations which we know before they occur. Examples: Calibration or validation is not carried out as per schedule due to delay for various reasons.
Unplanned deviation: Unplanned deviations, any change from previous or written procedure. These may have impact on product quality but not every time. Deviations observed as a result of incidences are covered under unplanned deviation.
Examples: Failure of procedure, utility, material, equipment, or any system.
On the basis of impact, planned deviation and unplanned deviation are categorized as follows
1
:
a.
Examples: Raw material is received in a damaged container. Manometer readings in the sampling booth has crossed the action limits.
b.
Examples: Production started without line clearance. Operational parameter out of range for a parameter defined as noncritical. Use of unapproved reference standard to test an active pharmaceutical ingredient (API) or drug product.
c.
Examples: Expired or rejected API component used. Wrong batch details are printed. Temperature out of control limit during detoxification stage.
Deviation decision tree 5
To decide and classify deviation, deviation decision tree is used. The deviation decision tree starts with event detection. After event detection, impact of deviation on manufacturing, process parameters, and SOPs/good manufacturing practice (GMP) is checked. If there is no impact, then it is an incident. If there is impact on manufacturing, process parameters, and SOPs/GMP or undetermined, then its effects on quality attributes need to checked. If deviation affects quality attributes then it can be major or critical deviation. If it does not affect then check its effects on operations and critical parameters, if yes then it can be major or critical deviation and if undetermined or no then check its effect on equipment or instrument associated to the process. If it does not affect then it is a minor deviation, if it affects or undetermined then it can be major or critical deviation.
CAPA
Identification Impact/Risk assessment Immediate action Root cause investigation Conclusion and quality decision Action plan Implementation and follow-up Identification: Define the problem: To enable an efficient root cause investigation, the problem has to be clearly defined. Collect all available information, ask questions: Who, when, what, why, how? Summarize the problem in a detailed and concise description. Impact/Risk assessment: Initial assessment of the impact and the magnitude of the problem. The evaluation should include:
CAPA methodology results in product and process improvements and enhanced product and process understanding.
Potential impact of the problem: Risk to its customers and/or the company (i.e. risk to the patient related to the quality, efficacy, or safety of the product; risk for the reputation of the company; risk of adverse regulatory actions; financial risk). Immediate action may be required.
For risk assessment, risk assessment tool matrix is used which is given in Table 2.
Risk assessment tool matrix.
H: high; L: low; M: medium.
iii. Immediate action: Immediate action is necessary, when the quality, efficacy, or safety may be compromised by the problem.
iv. Root cause investigation: Identify the root cause of the problem by using a systematic approach.
For investigations and root cause analysis techniques are given in Table 3.
Investigations and root cause analysis techniques.
v. Conclusion and quality decision
Final thorough conclusion on the impact and magnitude of the problem, decision regarding the use of the product, etc. Summarize the identified root cause(s). Summarize the impact and the risk for the customer and/or company. Document the quality decision.
vi. Action plan: Define CAPA
The plan assigns responsibilities and due dates for implementation. Enough detail must be included regarding the required action and the expected outcome.
vii. Implementation and follow-up
Implement corrective and preventive actions and verify their effectiveness (global approach).The action plan is executed and all tasks are completed. The actions that were taken are documented. The appropriateness and effectiveness of the actions taken is evaluated: Have all recommended changes been completed and verified? Have all objectives been met?
Application of CAPA 2 system throughout the product lifecycle is given in Table 4.
Application of corrective action and preventive action system throughout the product lifecycle.
CAPA: corrective actions and preventive actions.
Case studies for parenteral dosage form
Case studies of deviation, where CAPA is required.
Case studies of deviation, where CAPA is not required.
Case studies of deviation (CAPA).
CAPA: corrective actions and preventive actions.
During manufacturing of X drug injection (vial), at the time of collection of sample of T15 and T18 from 150 l storage vessel after filtration, the temperature of bulk solution kept for hold time study was found to be 13.7 and 14°C, respectively (acceptance criteria: 2–8°C).
At the time of collection of sample of T15 and T18 from 150 l storage vessel after filtration, the temperature of bulk solution kept for hold time study was found to be 13.7 and 14°C, respectively (acceptance criteria: 2–8°C).
Potential impact: Product may fail in hold time study results.
Risk to its customers: As the batch was a validation batch and manufactured for regulatory filing purpose, the batch was not for commercialization, and it was happened in hold time study bulk, hence there was no direct risk involved.
Temperature of circulated brine was higher than 8°C.
Informed to engineering department for further investigation.
Batch was manufactured as per approved master production control record (MPCR). Throughout the manufacturing process, 2–8°C temperature was maintained. At the time of API, addition temperature was 5.2°C. Batch manufacturing was completed on the same day. No discrepancy is observed during the manufacturing process. Hence, there is no impact on the quality of the product.
Filtration was performed between time duration of 08:52 and 08:58. Filling and lyophilized powder loading of vials was carried out between time duration of 10:33 and 14:32 on the same day. During filtration, filling, and lyophilized powder loading process of the batch, the temperature of circulating brine was found to be within limit (2–8°C). No discrepancy was observed during filtration, filling, and lyophilized powder loading processes.
During collection of hold time samples at T6 and T12 of unfiltered solution, the temperature of circulating brine was found to be within limit (2–8°C). At the time of collection of sample of T15, the temperature of bulk solution kept for hold time study was found to be 13.7°C on the same day at time 23:58. The temperature of circulating brine after collection of sample of T15 got increased from at time points T15 (13.7°C) to T18 (14°C) to T24 (8°C). Upon investigation, it was found that the temperature of brine chilling plant was above 8°C (acceptance criteria: 2–8°C) as the chiller was tripped due to compressor getting short-circuited. Compressor got short-circuited due to overheating.
Brine chiller has two compressors of 10TR. One compressor got sort due to overheating and second compressor is in series connection with another compressor, hence it got sort. One compressor of 10TR system which is in series connection started in 30 min after removing the cable of second compressor. For other 10TR compressor, miniature circuit breakers were replaced and the system started but still the compressor was tripping. The compressor body was found to be short and sent to vendor for rewinding. The temperature achieved was around 8°C from 11°C in 4–5 h from a single compressor of 10TR.
Brine chiller plant working details:
As both the compressor arc in series connection and tank of brine are common, it requires running both the compressors at a time for any use.
Based on quality control (QC) results, further action needs to be taken. The QC results are found to be satisfactory and there is no impact on the hold time study results.
Audiovisual alarm will be installed at the manufacturing tank operating panel to give audiovisual alarm in case the product temperature goes out.
To decrease the cooling time, we have proposed to close the partial partition (which is open) between brine tanks to make it a separate system. Arrangement will also be made to start system individually or simultaneously.
After completion of validation batch, audiovisual alarm is installed at the manufacturing tank operating panel so when the product temperature goes out, audiovisual alarm gets on.
The partial partition (which is open) between brine tanks is closed to make it a separate system. Arrangement is done to start system individually or simultaneously.
During manufacturing of Y drug injection (vial), slight pop up of the rubber stopper from some of filled vials (approximate 5%) is observed after stoppering.
Slight pop up of the rubber stopper from some of filled vials (approximate 5%) is observed after stoppering.
Potential impact: There is a risk of sterility failure of the batch.
Risk to its customers: As the batch was a validation batch and manufactured for regulatory filing purpose, and the batch was not commercialized, hence there was no direct risk involved.
The pop up rubber stoppers were pressed by using forceps on the conveyor belt before sealing.
The second batch was manufactured on the same day, in that batch also slight pop up of the rubber stopper from the filled vial was observed. So investigation was proceeded to find out the root cause.
Following probable causes were monitored for systematic investigation:
It may be the probable cause for pop up of rubber stoppers. Before start of second validation batch, the filling trial was taken with same vials and rubber stoppers as exhibit batch. There was no pop up observed and hence, the problem of pop up is not due to machine setting.
The type of vial could be another probable cause for the pop up as it may be possible that the dimension of vials may not fit with the rubber stopper or filling machine.
The vials used in exhibit batch (trial-1) are United States Pharmacopeia type I clear tubular glass vial. The filling (trial-2) was taken with vials and rubber stoppers as of exhibit batch. The pop up problem was observed during filling as same pattern as observed in first validation batch. The filling (trial-3) was taken with blow back (i.e. different type of vial) with the same rubber stoppers as exhibit batch. There was no abnormality observed during filling and the trial results were found to be satisfactory. The rubber stopper plugged and griped well in the vial compared with existing vials.
Hence, the existing vials may have an effect on pop up problem.
The type of rubber stoppers may be another possible cause for pup up.
The filling (trial-4) was taken with existing vials and rubber stoppers by filling water for injection (WFI). The pop up problem was observed during filling as same pattern as observed in the first validation batch.
Hence, the existing rubber stoppers without blow back vials may have an effect on pop up problem.
During observation, it was found that in the first validation batch, the sterilized rubber stoppers hold for long time (approximately A hours) before filling. It may be possible that the rubber stoppers get hardened after keeping for longer time after poststerilization and may not stopper well on the vials. So finally it may lead to pop up problem. Hence to simulate the observation of first validation batch, the effect of rubber stoppers’ hardness after autoclaving was studied by taking the following trials:
The filling (trial-5) was taken by filling WFI in existing vials and existing rubber stoppers kept for approximate A + B hours after sterilization. There is no pop up observed during filling and trial was found to be satisfactory.
For further confirmation, one additional filling trial (trial-6) was performed with usage of blow back vials with same rubber stoppers as exhibit batch. There was no abnormality observed during filling and the trial was found to be satisfactory.
From the above investigation, it is found that the combination of existing rubber stopper and vial without blow back is causing the pop up problem and combination of blow back vial with existing stopper is found to be satisfactory.
Based on the conclusion, following recommended action to be taken to overcome the pop up issue:
Existing rubber stopper and blow back vials. The third validation batch to be taken with the existing vials and rubber stoppers.
Filling activity to be monitored to minimize the pop up issue.
After completion of validation batches, the existing vials will be modified to blow back vials with same vendor and specifications for commercial manufacturing of the product. The blow back vial will be proposed for the commercial batches to remove the pop up problem.
During manufacturing of Z drug injection (vial), momentary drop in differential pressure was observed in aseptic area. Concerned officer/executive needs to decide whether it is planned or unplanned deviation.
Momentary drop in differential pressure in aseptic area.
Potential impact: Hold time of injection may be extended.
Risk to its customers: Hold time for filtrate was extended but not to the extent which affects product as per QC results.
Ampoule filling stopped and filled ampoule tray kept separate with proper status label.
All personnel left the affected room.
Filling activity not started on another line and filtrate kept in aseptic area in closed condition.
Checked aseptic area doors and were closed properly. Hence, the possibility of door open related cause is ruled out.
Checked fresh air damper positions and found to be well within range as per marked position. Hence, the possibility or disturbance in fresh air damper position is ruled out.
Checked motor was in working condition. Verified the operating panel and trip indicator was in “OFF” condition. No intimation for tripping of motor observed during the differential pressure drop duration. Hence, possibility of motor tripping is ruled out.
While motor was in operation it was observed that out of three drive belts, two drive belts were broken due to which rotations per minute of blower got reduced. This resulted in pressure drop in the area.
From the investigation it was observed that differential pressure in aseptic area got dropped as the two out of three nos. of drive belt of blower motor were broken.
During preventive maintenance every six months, V belt (drive belt) for all the sterile area will be replaced.
Task list of preventive maintenance of air handling units (AHUs) shall be revised through change request form (CRF) to incorporate V belt replacement for sterile area AHUs.
The SOP for the V belt change in aseptic area at every six months is created and followed.
After manufacturing of R drug injection (vial), repackaging to be done into packing configuration to 72 bottles per shipper from existing 144 nos. bottles—to cater client’s requirement.
Repackaging to be done into packing configuration to 72 bottles per shipper from existing 144 nos. bottles—to cater client’s requirement.
Potential impact: Product may fail in hold time study results.
Risk to its customers: The changes are relevant to tertiary packing material. Hence no impact on product quality, safety, and efficacy.
Batch will be taken back from bonded store room for repacking.
It was client’s requirement.
Repackaging, reconciliation, and change in MPCR.
Shipper opening activity performed in secondary packing area after line clearance.
De-packing to be performed as per de-packing MPCR.
Old packing material, i.e. shipper, poly bag, and plain label to be destroyed.
Batches shall be packed in existing batch no. since the primary pack remains the same.
New required packing materials will be arranged.
Line clearance procedure will be followed for repackaging.
Repacking activity to be recorded in MPCR.
Reconciliation will be done after completion of packing.
MPCR shall be revised for permanent change in the packing configuration as per the client’s requirement.
MPCR is revised for permanent change in the packing configuration for that batch.
Packaging is done as per the client’s requirement.
During manufacturing of S drug injection (vial), batch coating to be done using HK coating machine and provision of HK coating machine is not given in MPCR.
Batch coating to be done using HK coating machine and provision of HK coating machine is not given in MPCR.
Coating should be done on the coating machine which is mentioned in MPCR.
To utilize the newly installed HK coating machine.
Existing coater is engaged in coating of other products.
Proposed HK coating machine is having same class and subclass and similar working principle as that of existing coating machine.
Potential impact: May have impact on in-process parameters, finished product result and tablet appearance, cleaning validation, stability.
Risk to its customers: As the batch to be released after satisfactory acceptable quality limit (AQL), hence, there is no impact on safety, efficacy, and quality of product.
Stop the process at the point it is.
Severity is medium as all the in-process coating parameters to be kept as per approved limit only and batch size of the products lies within the qualified capacity of HK coating machine. Probability of occurrence is medium, the batch size is within the qualification range, and validated in-process parameter shall be used for coating process. Working principle of existing and proposed coating machine is same as per guidelines of scale up and post approval changes. Delectability is high as all the in-process parameters to be monitored as per frequency given in MPCR and in process SOP.
Coating to be performed on coating machine (i.e. HK coating machine).
Equipment ID no. for HK coating machine mentioned in current MPCR by handwritten entry.
All the process parameters to be monitored as per frequency given in approved MPCR.
AQL to be performed as per SOP.
Batches to be released after satisfactory finished product and AQL result.
Coating parameter to be followed as mentioned in MPCR.
After satisfactory result of finished product, MPCR to be revised through CRF for addition of HK coating machine.
MPCR was revised through CRF for addition of HK coating machine.
Checked the MPCR, HK coating machine is added in the revised MPCR.
Case studies of deviation (no CAPA).
CAPA: corrective actions and preventive actions.
Here only preventive actions are required because it is a one-time deviation.
During manufacturing of D drug injection (vial), batch packing activity was completed with batch coding details having 36 months of shelf life instead of 24 months.
Batch packing activity was completed with batch coding details having 36 months of shelf life instead of 24 months.
Potential impact: No potential impact.
Risk to its customers: The batches are kept under hold. Moreover, the product is stable up to 36 months. The 36 months’ shelf life is approved for other market. Hence it has no impact.
In “shelf life” 36 months was mentioned as reference to “shelf life” of same drug in different market.
Batches are kept under hold.
Repacking is done in new cartons in coding details 24 months of shelf life.
Training to the concerns imparted.
Repacking is done in new cartons in coding details 24 months of shelf life.
During manufacturing of E drug injection (vial), during visual inspection of the first exhibit batch, black particulate matter rejection was observed to be 2.43% (limit: black particulate matter limit: not more than 2.0%). Concerned officer/executive needs to decide whether it is planned or unplanned deviation.
During visual inspection of the first exhibit batch, black particulate matter rejection was observed to be 2.43% (limit: black particulate matter limit: not more than 2.0%).
Potential impact: Product may fail in particulate subvisible test.
Risk to its customers: As the batch was a validation batch and manufactured for regulatory filing purpose, and the batch was not commercialized, hence there was no direct risk involved.
After completion of visual inspection, optically good vials and rejected vials were segregated.
Optically good vials and rejected vials kept in 2–8°C with proper status label.
The following approaches were adopted for systematic investigation to find out the firm reason for black particles in the first exhibit batch:
The executed BMR was thoroughly reviewed for any deviations from the established manufacturing procedure. No deviation was observed during manufacturing.
The vials, which had developed black particles, were opened and the rubber stoppers were checked for any possible erosion and leaching. The rubber stoppers were found to be intact with no damage to the coating. Hence leaching from rubber stopper is not a possible reason for black particles. Also we have carried out trials to rule out the possibility of interaction with rubber stopper.
Clear type 1 glass vial was used in the exhibit batch, same source of vial was used in past exhibit batch for US market and there was no any black particles observation in batch, so interaction with vials was ruled out as a possible reason for black particles.
There could be a possibility that the change in source of propylene glycol and dehydrated alcohol used in batch manufacturing process may be the probable reason for black particles.
There could be a possibility that the black particles may be coming from the facility. To conclude above possibility, the following experiments were planned.
Visual inspection rejection details of previously manufactured US exhibit batch reviewed and rejection was found to be within acceptance criteria, so black particles’ generation from formulation was ruled out as a possible reason for black particles.
Based on the above investigation and trials, it can be concluded that the black particles are not getting generated from the product as the results are found to be well within limits.
As the black particle rejection is slightly higher than the set limit, final conclusion shall be drawn after next validation batch manufacturing.
The second validation batch was manufactured as per MPCR and visual inspection data were found to be satisfactory.
Visual inspection details:
Total of 2256 vials were filled which are visually inspected by qualified visual inspectors. There are total of 40 vials which were rejected during visual inspection process. At the end of inspection, sampling was carried out as per AQL and inspected batch complied with the acceptance limit.
The visual inspection rejection data were found to be well within the limit.
Both the validation batches kept for two months under observation and re-inspection to be done.
Packing shall be initiated based on re-inspection data of both the batches.
The re-inspection of both the validation batches was performed after keeping the good vials for approx. 4 months for first batch and approx. 2 months for second batch under observation and the inspection data found as under:
Visual inspection details (re-inspection):
A total of 1967 vials and 1970 vials were taken for visual inspection by qualified visual inspectors. There was no any vial rejected during the visual inspection process. The data of re-inspected batches complied with the acceptance limit.
The re-inspection data were found to be well within the limit and no rejection observed.
The particles are not generated after keeping the vials as nude condition for long time under 2–8°C.
There is no any assignable cause identified for slightly higher rejection of black particle in the first batch during first time inspection. It is the stray incidence observed in the first batch, hence no further CAPA required.
As re-inspection data of both the batches were found to be well within the limit, the packing activity to be initiated for both the batches.
During manufacturing of F drug injection (vial), one batch of 14 l is manufactured and further two batches to be manufactured with 14 l instead of two batches of 50 l. As per the United States (US) draft guideline, minimum exhibit batch size of 50 l is for abbreviated new drug application (ANDA) batches only and the batches are going to be taken for new drug application (NDA) so it is exempted from the guidelines.
Earlier CRF submission mentioning exhibit batch size 50 l as per new guidelines which is compulsory for ANDA not for NDA. So we have to file deviation to reduce batch size to 14 l.
Potential impact: There is no impact on existing MPCR, process validation protocol/process validation report (PVP/PVR) of 14 l batch size.
Risk to its customers: As the batch was a validation batch (exhibit batch) and manufactured for regulatory filing purpose, and the batch was not for commercialization, hence there was no direct risk involved. The commercial batch size shall be approved by the regulatory authority after submission. These are for NDA submission and not for ANDA, hence exempted from the US draft guideline for ANDA batches.
Further two batches to be manufactured with 14 l instead of two batches of 50 l.
New PVP/PVR to be prepared for 14 l batch size with two batches provision.
During manufacturing of G drug injection (vial), testing of stability sample to be extended. Concerned officer/executive needs to decide whether it is planned or unplanned deviation.
Stability samples may not be analyzed as per time interval mentioned in SOP due to increase in number of stability sample/month in current year as compared to earlier two years.
Potential impact: Samples that are at last station of accelerated (6 months), intermediate (12 months), and real time condition for final time point will be analyzed first. Remaining samples will be completed after four months of current year. So it has potential impact.
Samples that are at last station of accelerated (6 months), intermediate (12 months), and real time condition for final time point will be analyzed first. Remaining samples will be completed after four months of current year.
Testing of stability samples to be completed after four months of current year.
Testing of upcoming four-month samples to be completed by fifth month of current year.
Conclusion
Deviations are a part of pharmaceutical industry which are categorized based on its occurrence frequency and impact on final drug product. Deviations are handled as per their handling procedure which can be different in different industry but general action plan procedure remains the same. CAPA is used to make up that deviation and prevents its reoccurrence. In order to solve deviations, every organization has to have effective tools or techniques for investigation, to identify root causes and implement workable corrective and preventive action in a timely manner. CAPA system is used throughout the product lifecycle. Every deviation needs to be documented, so if in future same deviation was found with another drug, it facilitates the correction, prevention, and make process of CAPA faster. Case studies are stories which present realistic, complex, and contextually rich situations where dilemma and conflict are there which need to be solved. In this article, case studies of deviations in pharmaceutical industry helped in identification and evaluation of deviation and based on that application, a suitable CAPA is shown which gives thorough understanding of deviation and application of CAPA in pharmaceutical industry. An effective process should aim to promote critical thinking within the organization at all the levels. The process must provide a common model and risk-based framework within organization, which allows investigators to master the process quickly and easily. This would anchor common logic behind investigations and bring unity to problem solving. CAPA saves extra work, time, and money invested in pharmaceutical industry. So, CAPA is not only regulatory requirement but it makes good business sense to pharmaceutical industry.
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.