Compliant QC Laboratory - 13 Key Elements To Focus On

Compliant QC Laboratory

Quality control laboratory is an important function and plays a critical role in building the quality of pharmaceutical drugs and products. The efficiency of the laboratory and its compliance with regulatory requirements such as GLP and cGMP plays a vital role in protecting the patient's life.

The sophisticated instruments with secured software and brilliant analytical chemists with good qualifications will bring reliability and best quality into the medicinal products.

Compliance of QC Lab with regulatory requirements is one of the essential needs to fulfill by a pharmaceutical company .

I think, there is no need to repeat the impact of warning letters on the pharmaceutical companies. Majority of the warning letters were issued due to the weak governance or poor maintenance of the QC Lab.

There are multiple reasons for this bad situation. In some laboratories, there are no controls on generation and deletion of data and in some other laboratories purposefully tampering the data taking the advantage of loopholes in the software or system.

Hence, now it’s the time to build a compliant laboratory which increases the company's pride. For that, you need to take a systematic approach. Proper planning and unshakable determination to reach the goal is essential.

Company's management has to take a strong commitment to protect the laboratory's freedom to give the decision on the product's quality with transparency.


There are 13 key elements to focus on for a better compliant QC laboratory. Let us look into each of them.


1. Laboratory Physical Conditions

Laboratory Physical Conditions


The very first thing, you need to take care of, is adequacy of facilities in the laboratory.

The design of the laboratory should accommodate easy and safe operations in a day to day's work.

The laboratory should have minimum facilities as mentioned below.

  1.   Good ventilation with fresh particle free air circulation system.
  2.   Sufficient space to move a fire-engine freely around the laboratory.
  3.   Lighting in the laboratory should support visual related tasks.
    §    Lighting arrangement should be based on the room size and the type of work to be carried out in the room.
    §    The light should be uniform throughout the room.
  4.   Separate room with adequate space for the storage of chemicals.
  5.   Adequate facility for the handling of hygroscopic and oxygen sensitive materials.
  6.   Separate room with adequate space for glassware cleaning, drying and storage.
  7.   One room to conduct training for the employees.
  8.   Separate controlled area for the servers which connected with the lab equipment.
  9.   Independent room for weighing balances with full air controls and anti-vibration facility.
  10.   Adequate space for stability chambers and adequate size of stability chambers.
  11.   Independent facility for the storage of new glassware and lab equipment spare parts.
  12.   Separate and adequate facility for retention samples (reserve samples).
  13.   Controlled room for the storage of reference standards and working standards.
  14.   Safe area for gas cylinders.

Spacious laboratory with sufficient ventilation gives much comfortability to the laboratory personnel. It avoids many unsafe conditions in the lab and saves the company's property. The lab design should be made based on the type and nature of analytical tests intended to perform.



2. QC Laboratory Safety

Lab Safety


Lab safety has primary importance among all the lab related activities. Safety is the foremost thing to take care of each and every minute you move in the lab.

Everything will turn into ash within seconds even for small negligence or mistake. A cost of a mistake can be anything including human death.

Lab personnel use a lot of variety of chemicals in the lab. Hence, the management of laboratory chemicals is the first thing to focus on. A compromise in lab safety leads to an unimaginable loss and destruction.

Ensure the following safety measures.

  1.   Segregate and store the chemicals based on their chemical and physical properties. Organize them based on their compatibility.
  2.   Arrange a First Aid box in the laboratory.
  3.   Provide adequate and sufficient Personal Protective Equipment (PPE) to the employees.
  4.   Define safe handling procedures of hazardous chemicals and ensure the availability of Material Safety Data Sheet (MSDS).
  5.   Always read MSDS carefully and wear appropriate PPE before proceeding to handle them for analysis.
  6.   Take remedial actions to eliminate the interaction of static electricity with chemicals.
  7.   Define safe handling procedures of gas cylinders.
  8.   Define chemicals transportation procedures, to move them from stores to the lab.
  9.   Use flame-resistant safety cans for safe handling of flammable liquids.
  10.   Use fireproof cabinets to store flammable chemicals.
  11.   Install smoke detectors in the lab.
  12.   Immediately record all safety-related incidents and investigate. Implement the CAPA as soon as possible to prevent the recurrence of the incident.
  13.   Keep eyewash bottles in all corners of the lab and arrange one head shower system in an easily accessible area of the lab.
  14.   Educate the lab personnel on the use of first-aid-kit and PPE use.
  15.   Regularly remind the employees about the location of first-aid-kit and PPE in the lab.
  16.   Prepare a general lab safety audit checklist and conduct the audit daily for the identification of unsafe conditions and adequacy of PPEs. Make it mandatory that every employee in the lab should conduct the safety audit, at least once in a month, using this checklist.
  17.   Train the employees on "How to respond in emergency situations and fire accidents?"

Lab safety is an important aspect which grabs the attention of regulatory agencies naturally because it impacts the drug supply into the market. Any major fire accident can lead to a huge property loss and halt in the manufacturing activities. If this happens, a shortage of drug availability arises in the market and poses a threat of death to patients.



3. Analytical Equipment

Analytical Equipment

QC laboratory uses many kinds of equipment to test the quality of materials. Different types of instruments and a lot of their manufacturing companies are playing a key role in drug analysis.

The role of analytical equipment, in determining the quality of a product, is enormous and includes many technical aspects.

Generally, laboratories will procure instruments, which offer versatility in employing them for different analytical techniques, based on the need for analytical tests.

The level of sophistication, maintenance and its capability to extend the scope of testing to look into the details are the key factors in the selection of analytical equipment. Analytical equipment has a direct relationship with a drug's quality testing.

There are 4 important elements, which need your attention, to make your lab compliant w.r.t., analytical equipment. Check whether the below-listed things are ready or not, in each element, to show the regulators. If not, make them ready before you start the testing of materials.

a. Qualification of Equipment/Instrument

  1. Prepare an SOP for the installation and qualification of equipment/instrument.
  2. Get the Purchase Order of the equipment.
  3. Perform DQ, IQ, OQ, and PQ for the equipment.
  4. Get the calibration certificates of other analytical aids such as thermometers which are used in the process of equipment qualification.
  5. Get the certificates of reference standards which are used in the process of equipment qualification.
  6. Investigate IQ, OQ, and PQ failures during the installation, if any. Make a report along with the implementation of CAPA.
  7. Make available instruments' manuals at the workplace.
  8. Define when the requalification of instrument/equipment is needed. Example: After 5 years from the purchase of instruments; perform PQ whenever a critical part is changed.

b. Validation of Software which operates Equipment/Instrument

  1. Prepare an SOP for the validation of software.
  2. Get the Purchase Order of the software.
  3. Perform software Validation after immediate installation of it on the hard disk.
  4. Make ready the documental evidence for the software validation.
  5. Define in what instances the software reinstallation and revalidation is required.

c. Performance Verification/ Calibration of Equipment/Instrument

  1. Prepare an SOP for the Performance Verification / Calibration of Equipment/Instrument.
  2. Prepare Performance Verification / Calibration procedure in such a way that it should involve all the critical components in measuring the accuracy and linearity of the equipment.
  3. Define the frequency of calibration for each instrument and prepare instrument wise calibration schedule.
  4. Clearly define what to do in case of Performance Verification / Calibration failure.
  5. Define the scope of investigation in case of Performance Verification / Calibration failure.

d. Maintenance of Equipment/Instrument

  1. Prepare an SOP for the preventive maintenance of Equipment/Instrument.
  2. Define the role of the in-house service engineer.
  3. Prepare Equipment/Instrument wise checklist to conduct preventive maintenance.
  4. Prepare a list of critical parts for all equipment.
  5. Define a period or criteria for the change of critical parts.
  6. Prepare a list of consumable parts for all equipment.
  7. Define a period or criteria for the change of consumables.
  8. Maintain history sheet for all equipment.
  9. Periodically assess the health of equipment, based on the history of repairs and calibration failures, to judge whether the equipment is fit for the use of routine analysis or not.

Regulators have special attention on the analytical equipment since it's the primary source in the process of drug quality determination. The accuracy of the test result depends on the performance of the equipment and software/firmware.



4. Analytical Chemist

Analytical Chemist


Analytical chemist or lab technician is the main pillar for the QC Laboratory. He certainly requires skills such as concentration, understanding, observation and writing, to carry out the test without errors. His educational qualification, honesty and sharp intelligence are the driving forces of the laboratory. The ability of the QC person, to conduct a test with accuracy, will influence the final test result of a product.

Medicinal products will enter the market only after getting a certification from the QC laboratory. Hence, regulators give much importance to the analytical chemist's activity and his performance. They may observe the analyst while performing a test on the product during their inspection.

The following things must be available at the laboratory to meet the regulatory requirements.

  1. An SOP for the training of new and experienced employees.
  2. Proficiency testing of analytical chemists.
  3. Annual Schedule for cGMP and other technical training along with evaluation.
  4. Training on analytical methods, general SOPs, and Performance Verification/ Calibration of Equipment/Instrument along with evaluation.
  5. Training on laboratory safety, handling of chemicals and First-Aid treatment.
  6. A comprehensive procedure for the qualification of analytical chemists.
  7. Qualification record of the analytical chemist for each test he is performing in the lab. In case he fails in the qualifying test, asses the reasons and takes corrective actions. After retraining, reconduct the qualification test. Document everything.

Regulators, generally spend more time to verify QC related activities during the inspection. Because it's the main source for the assessment of a product's quality and efficiency of the manufacturing process.



5. Analytical Method.

Analytical Method

The analytical method plays an important role in the judgement of drug quality. You must select an appropriate method for the testing of materials. An inefficient test method will certainly give wrong results and mislead you from the actual estimation of the product's components. This will ultimately harm the patients and becomes a potential threat to their health. An example is the 2008 - Heparin disaster.

So, being aware of this dangerous threat, regulatory bodies set forth a lot of requirements under cGMP w.r.t., analytical methods. You must prove that the analytical method you used is appropriate and produces accurate and reliable results every time you employed it. You must generate documental evidence for your analytical method's capability, to demonstrate it's suitability for routine testing.

Ensure whether you are meeting with the below-given requirements or not.

  1. An SOP for the development and validation of analytical methods.
  2. Every method should have a development report which describes how it was optimized.
  3. Every analytical method must be validated and documented.
  4. If you are using compendial methods, you must have to verify that method in your laboratory environment. You must assess the method by subjecting it to your actual laboratory conditions i.e., verify the method with the chemicals or HPLC/GC columns that generally available to you. If any slight modifications are required, you can do it within the allowable range given in pharmacopoeias. If the changes cross the allowable range, then you need to go for full method validation.
  5. Do the compendial method verification as suggested by the pharmacopoeias and document it.
  6. Prepare an SOP for writing an analytical method for routine testing.
  7. Write the test method in a simple language which can lead the analytical chemist to no confusion. Define all the steps very clearly and leave no room for ambiguity.

    Observe the below example.

    Statement : Sonicate the solution for a few seconds.

    This statement is not clear. It's a vague statement. An analytical chemist really don't know how many seconds he has to sonicate the solution. In such situations, people will interpret things in their own way. One person would sonicate the solution for 10 seconds and another person will do the same thing for 20 seconds.

    Then there will be no uniformity in the testing.

    Hence, you have to write the statement as: Sonicate the solutions for 20 seconds. Don't apply heat.

  8. Provide a preprinted raw data form (blank form) to analytical chemist, to record the analytical data during the testing. The analyst should not rely on his memory power. It is impossible to remember hundreds of methods. The blank form of Raw Data should guide him on the procedure he has to follow.
  9. You need to reassess the analytical methods' performance periodically, especially HPLC/GC methods. Why because the changes in the composition of HPLC/GC packing, during the columns' manufacturing at different times, may impact the resolution of some impurities. The effect may be of either non-detection of existing impurities or detection of entirely new impurities in the product.

The existence of a drug's quality is totally dependent on the design and performance of the method. An inefficient or improper analytical method will never produce reliable and accurate results.



6. Documentation

Documentation


Reliability on QC Laboratory always stems out from its documentation practices. Information and evidence for a product's quality will be available, only in QC documents.

Improper documentation of QC activities will attribute no value and sanctity to the testing of a product.

Therefore, you must remember that your QC Laboratory's documentation practices will judge your company's commitment to bring transparency in the business.

Ensure whether you are meeting with the below-given requirements or not.

  1. Have an SOP for good documentation practices.
  2. Record all the activities at the same time they are occurring.
  3. Maintain log books for all analytical equipment and instruments. The entries should be in chronological order.
  4. Record all lab incidents as and when they occurred.
  5. Record all OOS/OOTs immediately, to facilitate further investigation before the pieces of evidence are lost.
  6. Prohibit overwriting and use of white markers to erase details which are already documented.
  7. All documents must contain the signatures of performer and reviewer along with date and time.
  8. All your blank forms, SOPs, STPs and guidelines must contain a unique form number and version number.
  9. All your blank forms, SOPs, STPs and guidelines must contain a revision history to understand the past changes.
  10. Use controlled documents only, i.e., documents approved by QA.
  11. Prohibit the use of scrap paper for a temporary recording of details.
  12. Manage any amendment or revision of the document, through the Change Control system.
  13. Have an SOP for the review of analytical documents. Describe in it how to review various kinds of documents in QC Laboratory.
  14. Ensure that all obsoleted documents are immediately moved to QA for destruction purpose. Set up a permanent system to monitor this activity.
  15. There should be a proper mechanism to monitor and ensure the arrival of documents to QC before their effective date. All the relevant QC personnel must be trained on the new documents/forms/procedures before their implementation.
  16. The entries in handwritten documents must be clear and legible. If any mistake happens, clearly strike through it with a single stroke and enter the correct one along with justification. Put signature with date.

Your documentation practices are your quality culture's indicators. Remember, regulators issued many warning letters based on QC Laboratory data. Eliminate all malpractices immediately and hold the flag of transparency.



7. Data Integrity

Data Integrity

I think there is no single person today, who has not heard of 'data integrity', on the globe. These are the two words which have shaken the whole pharmaceutical world.

Many pharmaceutical giants received a blow from the regulators due to data integrity issues. Pharmaceutical business was affected in an enormous way due to the warning letters caused by data integrity.

Data integrity is just as important as the data generation. You must ensure that you are delivering decisions based on accurate and reliable data. This is the primary responsibility of the QC laboratory.

Ensure the below-given requirements to protect your Laboratory's data integrity.

  1. Have an SOP to protect the data integrity inline with your company's data integrity policy.
  2. Generate data only from calibrated instruments.
  3. Allow only qualified analytical chemists to test the materials or products.
  4. Record the data only on QA approved and issued forms.
  5. The electronic records should comprise a complete set of details.
  6. The electronic data must be self-consistent.
  7. All the electronic data must be generated from a validated software.
  8. All the electronic data must be attributable.
  9. All the electronic data must be legible and permanent.
  10. All the electronic data must be a true copy of the original data.
  11. All the electronic data must contain metadata.
  12. Enable audit trail function in all software.
  13. Don't use shared login accounts for any kind of software.
  14. Establish access controls in all software and computers.
  15. Don't provide administrative rights to QC personnel for any software.
  16. Assign administrative rights and data backup responsibility to your corporate IT department.
  17. Disable recycle bin in all computers of QC lab.
  18. Remove the option of data deletion from all software. It should not be available to any QC personnel.
  19. Restrict the access to the folders on computer hard disks.
  20. Record the justification for the multiple processing of chromatography data files.
  21. Put restrictions on manual integration of chromatographic peaks.
  22. Establish a second competent person review system, wherever the data is to be entered manually and the entries are completely dependent on the person's discretion.
  23. Validate all your excel spreadsheets if you are using them for calculation purposes.
  24. Validate all your electronic calculators which are used for calculation purposes.

The confidence of regulatory inspectors on QC laboratory depends on the integrity of QC data. Data integrity issues can have serious consequences. Maybe they can permanently close your company's future.

Refer the following webpage for more details on data integrity.

US FDA Guidance : Data Integrity and Compliance With Drug CGMP



8. Laboratory Chemicals and Reagents

Chemicals and Reagents

Chemicals and reagents play a significant role in the analysis of pharmaceutical products. Their purity and quality have topmost importance in the testing process of materials.

The laboratory testing is broadly a mixing of different chemicals and solvents in a certain ratio, to find out the components of a given compound, either in a direct way or indirect way using various principles of separation, heat, light and electricity.

Hence, the quality of chemicals plays an important role in getting accurate results.

Ensure the following things to increase the confidence of regulators on your analysis.

  1. Maintain the best inventory management system. Do reconciliation of all chemicals from time to time. The quantities used for the analysis should match with the details of your inventory. Otherwise, it will give the wrong impression to the regulators and they will suspect your lab activities.
  2. Use only high purity (>99.9%) chemicals in laboratory testing.
  3. Don't use chemicals beyond their expiry date. Check the stock on daily basis and remove the expired chemicals.
  4. Have a proper labelling on the containers/bottles of solid and liquid chemicals. The label should indicate the date of expiry or the allowed period of usage.
  5. Keep hygroscopic materials in airtight and dry storage cabinets.
  6. Record the stability issues of chemicals, if you face any brands, and communicate the manufacturer immediately. If the issue is not resolved, ban them permanently.
  7. In case, impurities from the chemicals are interfering with the product's analysis, identify them instantly and document the investigation. This is a frequently observed case in HPLC/GC analysis. In such instances, put a note in the STP and avoid repeated investigations on the same issue.
  8. Create a suitable environment at the workbench, to keep the chemicals in a safe mode and to protect their originality, during the analysis. The chemicals should not lose their original quality after dispensing them from their storage area to workbench.

Quality of laboratory chemicals and reagents has a direct impact on the product's analysis. Therefore, you must continually evaluate your suppliers and send feedback.



9. Investigation of OOS/OOT/Incidents

Investigation of OOS

The numerals of OOS/OOTs can reveal many things about your manufacturing plant.

The higher the number of OOS - due to process failures, the lower the efficiency of the plant - to manufacture a product. Similarly, the higher the number of invalid OOS - due to lab errors, the lower the efficiency of the lab - to conduct testing.

So, this is the main reason for FDA's concentration on OOS/OOT or incidents, in every inspection. They give a lot of information on analytical equipment's health, skills of analytical chemists, adequacy of procedures and effectiveness of training.

Hence, the structure of investigation and scientific conclusion of a failure or deviation will fall under the regulatory scan very naturally.

Ensure the following things, to increase the confidence of regulators, on your lab investigations.

  1. OOS/OOT and 'Handling of Incidents' SOPs must be comprehensive in all angles. SOPs should clearly mention the steps of investigation and batch/lot disposition after the investigation.
  2. Maintain separate log books for OOS, OOT and incidents.
  3. Record all OOS, OOT and incidents immediately and don't delay the investigation.
  4. Keep and protect all evidence till the completion of investigation and declaration of batch/lot status.
  5. Do the investigation scientifically; follow logical steps. Don't imagine the causes for the failures or deviations and put them in the investigation report.
  6. Conduct the investigation based on the available evidence and use logical methods. Collect all the possible information and pieces of evidence; analyze them to find out the root cause.
  7. Don't stick to one investigation model. No one model is complete. Look into different models and check which combination of models can help you most in the investigation.
  8. Your aim is to find out the root causes for the failures or deviations and not to follow any single investigation method. Different types of failures need a different kind of investigation methods. There is no single universal investigation method.
  9. Conduct remeasurement of initial test solution in the same analytical environment as part of the preliminary investigation. This helps you to judge whether there is a laboratory error or not.
  10. Record the interview of an analytical chemist in the investigation report.
  11. Proceed for retesting with a new portion of the sample, only when there is strong evidence for the errors or deviations in the initial analysis. Testing into compliance is not at all acceptable.
  12. Resampling is allowed with precise justification, only when you have any evidence that the collected initial sample is not representing the original batch/lot. In this case, you need a thorough investigation of your sampling method too.
  13. Clearly define the retest plan. Mention how many test runs are required to conclude the OOS/OOT and incidents.
  14. Don't take the average result from the retesting run set, to declare the batch status.
  15. Declare the batch/lot status as "Failed", even a single test run fails in your retest plan.
  16. Invalidation of an OOS result, based on laboratory error, needs clear cut evidence; a mere suspicion will not make any value.
  17. Clearly define in the SOP, in how many days the investigation to be concluded.
  18. Investigate all unknown peaks in GC chromatogram, excluding blank interference peaks. Mention the need for unknown peaks' investigation in the appropriate SOP, either in OOT or Lab Incidents.
  19. CAPA management is the heart of your investigation system. The decrease in the occurrence of OOSs indicates the strength of the CAPA you have implemented. So derive perfect CAPA.
  20. You need to implement the CAPA across your organization, to prevent the recurrence of the same failure at other places.

The way you investigate, the capability to investigate complex failures, the methods you adopted for the investigation, the attitude to bring the transparency in the investigation and the strength to derive appropriate CAPA will play a critical role in getting the confidence of regulators on your laboratory.

Refer the following webpage for more details on OOS investigation.

US FDA Guidance : Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production



10. Stability Studies

Stability Studies

The whole pharmaceutical business is dependent on the stability of products manufactured in the plant.

The ability of the product, to retain its originality against worst environmental conditions, is the game-changing factor in getting the regulatory approvals.

Hence, regulatory authorities obviously give importance to the review of stability studies. They will verify all the facilities and systems related to the study of the stability of products. They may examine the design of your stability study program. So it is necessary to maintain the standards to meet the regulatory requirements.

Ensure the following things, to increase the confidence of regulators, on your stability studies.

  1. Have a detailed SOP for the study of the stability of products.
  2. Design the stability program fulfilling the requirements of all tropical conditions.
  3. Install the stability chambers with adequate size. Qualify the stability chambers.
  4. There should be standby stability chambers to face the situation of existing chamber's failure.
  5. Define a clear roadmap to avoid the confusion and make the process smooth to conduct the stability studies. Include the following things in the roadmap.
    i. The trigger or initiation of stability study (ex; new process, reprocess).
    ii. Type of stability study.
    iii. Qty of the sample to be collected.
    iv. Packing method of stability samples.
    v. Verification of Stability Study initiation by QA/CQA.
    vi. Schedule for the testing of stability samples.
    vii. Evaluation of stability study results.
    viii. QA/CQA Approval for the final stability study report.
    ix. Finalization of a retest or expiry date.
  6. Verify the performance of stability chambers periodically.
  7. Record the temperature and humidity of the stability chambers daily at a predefined interval. Record the data of all sensors.
  8. All excursions of temperature and humidity shall be investigated immediately and precautions shall be taken to protect the integrity of the samples. If required change the samples into the standby chamber.
  9. All stability failures should be thoroughly investigated. If the impact of OOS falls on the retest or expiry period of the product, you should immediately evaluate the risk and inform the customer or regulatory authority accordingly based on the situation.
  10. Restrict the entry into stability chambers. Only authorized people should be allowed into chambers. Log the people's movement into the chambers.
  11. Log the stability samples' arrival, release (for testing) and disposal. Record all your observations on packaging material's quality, as soon as you notice any abnormal change.
  12. Define the criteria when to and in what situations the stability studies shall be discontinued.

Stability study is one of the focused areas of Regulatory Agencies. The regulators will dive deep into the details of the product's failures and stability chamber's failures to understand the impact of them on product's expiry or retest period. Hence you must be very careful in conducting the stability studies.

Refer the following webpage for more details on Evaluation of Stability Data.

US FDA Guidance : Q1E Evaluation of Stability Data



11. Management of Reference Standards, Working Standards and Impurities Standards

Reference Standards

A reference standard is a backbone for any laboratory's analysis. Analytical testing depends on the principle of comparison. Generally, we declare the test results in comparison with reference material either directly or indirectly.

For example, caffeine is used to verify the performance of an HPLC instrument.

The margin of error can be understood by the use of reference material. Thus, reference standards help in the estimation of a true result of a given compound.

On the other hand, impurities standards are used as markers to identify them in the manufactured lot/batch. So, the purity and integrity of the impurity standard are the crucial things which have to be maintained its entire lifetime.

Ensure the following things, to increase the confidence of regulators, on your stability studies.

  1. Have a detailed SOP for the storage and distribution of reference standards, working standards and impurities standards.
  2. Provide MSDS and required PPE for all materials.
  3. Provide Certificate of Analysis (COA) for all materials.
  4. Store the materials under controlled temperature and humidity conditions.
  5. Monitor the temperature and humidity of the storage area daily.
  6. Repack carefully after the distribution of the material to routine work.
  7. Define procedure and have a separate facility to handle the hygroscopic materials.
  8. In the case of working standards, which are prepared using a manufacturing lot, the material shall be packed in the same packing conditions of that particular product.
  9. Elaborate the precautions to be taken and the necessary things to be performed, with these materials, before proceeding for analysis.
  10. Handle and store the Pharmacopoeia standards as directed in their Certificate of Analysis (COA).
  11. Review the validity status of Pharmacopoeia Standards periodically and ensure that always the current lots are in the laboratory's use. Document the review of Pharmacopoeia Standards' validity period.
  12. In-house reference standards should be characterized to prove their identity.
  13. You must establish retest or expiry period for all in-house reference standards, working standards and impurities standards.

Wrong usage and improper handling of reference standards, working standards and impurity standards will lead to erratic results. Now it is crystal clear that the negligence or imperfect handling of these materials will directly impact the quality of pharmaceutical products and harm the patient. Hence, it is absolutely necessary to maintain and protect the originality or integrity of these materials at all times. Otherwise, you are putting your business at greater risk.

Refer the following webpage for more details on Pharmaceutical Reference Standards.

EDQM Presentation : PHARMACEUTICAL   REFERENCE   STANDARDS



12. Maintenance of Glassware

Lab Glassware

Can you imagine a laboratory which works with no glassware? It's impossible for me. I think, you too have the same feeling.

Glassware is an inseparable part of a laboratory. The quality of glassware and its maintenance can affect the total analytical process.

Majority of the laboratories use Borosilicate glass which is made of silica and boron oxide. This Borosilicate glass is resistant to high temperatures and corrosive materials.

As the glass has a natural tendency to expand at higher temperatures, storage of laboratory glassware at a proper temperature, is mandatory.

Ensure the following things, to increase the confidence of regulators, on your glassware maintenance.

  1. Have a detailed SOP for the storage, cleaning and maintenance of the glassware.
  2. Clearly write the instructions in the SOP, on the way of usage of new glassware.
  3. Design a perfect cleaning or washing method for the used glassware.
  4. Use the cleaning method, only after the completion of its validation.
  5. Ensure that your cleaning method is capable to remove the stains of cleaning agents from the inner and outer surface of all kinds of glassware.
  6. Dry the cleaned or washed glassware at an appropriate temperature, maybe at 60-degree centigrade.
  7. Calibrate burette and pipette which are used in volumetric analysis.
  8. Use Class-A volumetric glassware only, in all types of quantification tests.
  9. File the certificates of all Class-A volumetric glassware at one place. You should get the certificates for each and every piece of Class-A volumetric glassware.
  10. Use Class-B glassware for general purposes.

The dirty glassware can give erroneous results. You must wash the glassware immediately after use. The ineffectiveness of the cleaning method will deeply affect the reliability and accuracy of your test results.



13. Product Sampling Method and Management of Retention Samples

Product Sampling

As everybody knows, sampling is the most important critical step to execute with due care, in the drug analysis. It is a method which is employed to collect a portion of the product to determine the drug's quality.

The sampled material represents the whole lot/batch. For this reason, the integrity of sampled quantity plays a vital role, in determining the quality of pharmaceutical drugs.

You should design a perfect sampling method which must have a scientific basis. You must generate documental evidence, to prove the collected material is truly representing the whole lot/batch.

Ensure the following things, to increase the confidence of regulators, on your sampling plan and method.

  1. Define how many containers the material needs to be sampled.
  2. Define how much quantity is to be taken from each container.
  3. Define the procedure of making a homogeneous composite sample, by mixing the sampled portions of individual containers.
  4. Validate your sampling procedure and use statistical methods to establish the confidence level and degree of precision.
  5. Elaborate the steps of sampling methods, for both solids and liquids.
  6. Determine the sampling quantity considering the retention sample requirements.
  7. Define which sampling tool to be used for the collection of the sample.
  8. Perform the sampling activity of hygroscopic and oxygen sensitive materials in a suitable environment which protects sample integrity.
  9. Define what environmental conditions the sampling activity shall be carried out.
  10. Pack the sampled material in the same packing conditions of the product being sampled.
  11. Establish a perfect cleaning method for the cleaning of sampling tools and validate it.
  12. Provide instructions or precautions to be taken before sampling, to prevent contamination during the sampling activity.
  13. Give clear instructions in the sampling procedure on opening, sampling and resealing of the containers, to prevent the contamination of the product.
  14. Define what care needs to be taken while collecting the sample for microbial tests.
  15. You need to train and qualify the samplers, i.e., the persons who are going to perform the sampling activity.
  16. There should be a sampling record to document the activity.
  17. The samplers should record the sampling details such as a total number of containers, the number of containers sampled, the identification number of sampled containers and the quantity collected from each container.
  18. The sampler should record if he observes any abnormality with the containers such as breakage of tamper-proof seals, deterioration and labelling abnormalities.
  19. The sampler should record the abnormalities with the material such as colored particles or oil drops in the material, solid material in liquids and big lumps in powder.
  20. Never return the material into the bulk quantity. Discard the excess material as laid down in the waste material disposal procedure.
  21. Supervise the sampling activity of each lot and take the supervisor's signature on each lot of sampling record.
  22. Your sampling record should reflect the purpose of the sampling i.e., for the purpose of routine testing or stability study or Regulatory Queries or developmental studies etc.

After making a composite sample, you need to preserve part of the quantity for future purposes. This preserved quantity is called retention or reserve sample. Keeping of retention sample with sufficient quantity is a regulatory requirement. This will help in resolving the disputes of analytical results from customers or regulatory agencies.

Ensure the following things, to increase the confidence of regulators, on your retention sample management.

  1. You must collect the sample at the same time along with the initial sampling of lot/batch.
  2. You must pack the material with the same packing conditions that do apply for the product at the manufacturing unit.
  3. You must keep the material in the original container that used for the product at the manufacturing unit.
  4. Store the retention sample at least one year after the expiry date.
  5. The quantity of the retention sample should contain enough size, to facilitate complete analysis of the lot twice, as per your release Specification and STP.
  6. Store retention samples in a similar environment of product storage at manufacturing unit.
  7. You must qualify the retention samples' storage area for its suitability to the intended purpose.
  8. Maintain a log book for the retention samples and place it always in the storage room.
  9. You must record the details of retention samples such as their arrival into retention sample room, their usage and disposal.
  10. Periodically review the samples and verify the condition of packaging material and the appearance of the material. Record your observations. If you notice any abnormality in the nature of packaging material and product, start the investigation immediately involving QA and manufacturing departments.

Refer the following webpage for more details on Retention Samples.

EU GMP : Annex 19: Reference and Retention Samples

The sampling of pharmaceutical drugs and the management of retention samples - these two key activities attract regulators highly. The scientific justification you documented for your sampling method, may be subjected to severe scrutiny just because this is the primary step in the drug's analytical testing process.

Retention samples are the only authentic sources which help you in resolving the issues with the product's quality after its distribution into the market. Hence, management of retention samples is necessary and it's a regulatory requirement.



Summary

There is no doubt that the compliance of the QC Laboratory can change the fate of a pharmaceutical company forever. From the lab design to test release, the laboratory needs to pass through many regulatory requirements.

Many stringent rules apply to QC Lab since it is providing a certificate of analysis to release the product into the market. Lab performance has a direct relationship with the patient's health.

Lab safety measures will protect the physical property of the company and human lives from major disasters. Storage and arrangement of chemicals as per their compatibility will save the lab from many incidents.

Well qualified analysts and perfectly designed analytical methods always yield accurate and reliable test results. The ability of an analytical chemist and the efficiency of analytical equipment are very important in the day to day analysis of pharmaceutical drugs. Hence, the qualification of an analytical chemist and analytical equipment is a necessary requirement.

Use only the scientifically proved sampling method to collect the representative sample for lot/batch analysis. Clearly mention the type and size of sampling tools to be used in the sampling process. Sampling shall be done by the qualified samplers only.

Qualify the reference standards, working standards and impurity standards as per the requirements. The integrity of these samples has a lot of influence on the entire analysis of the product. Bring awareness among the employees on the maintenance of these materials and the impact of their inferior quality on the analysis.

The next important things are good documentation and data integrity. Your documentation style and measures to the protection of data integrity will reflect your organization's culture. All activities shall be recorded contemporaneously. There should not be any intentional manipulations or modifications to pass the lot/batch to facilitate the business.

Conduct the stability studies as per the regulatory requirements. Acquire sufficient place for the construction of stability chambers. Maintain the stability chambers with utmost care and investigate all deviations on-time.

Investigate all lab incidents and product failures in a fair manner. Analyze the root causes and derive a perfect CAPA which can prevent the recurrence of failures. Have a strong justification for resampling or retesting.

Procure only high purity chemicals and reagents for the laboratory analysis purpose. Interference of impurities in the cheap chemicals may interfere in your analysis and thus will lead to erroneous results. Similarly, use Class-A glassware for analytical purposes and Class-B glassware for general purposes to reduce the margin of error in test results.

Retention samples' management is a regulatory requirement. Store the samples in market simulated conditions. Qualify the storage area and monitor the room daily by measuring temperature. Use the retention samples, only for resolving the quality issues, related to customers or regulatory agencies.

QC laboratory is responsible to deliver unbiased services. The level of compliance you are meeting with will decide the level of confidence of regulators you are going to get.



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Author Profile

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Ram Kumar Reddy

Ram Kumar Reddy is the founder of Pharma Times Now. Helping Pharmacy and Chemistry students, along with the pharma employees, in learning pharmaceutical science. He has 24 years of rich experience in the Pharmaceutical industry and well versed in quality systems. He worked with Dr.Reddys and Sai Life Sciences. He lives in Hyderabad, India.

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