Month: May 2020

Post-approval changes in the US

Changes to products licensed by the US FDA are achieved via the provision of supplements to the original new drug application (NDA).

AR: Annual Report

Changes that can be submitted in an annual report are of a minor in nature and that have minimal potential to cause an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.

 The affected product can be distributed at any time after the change has been internally approved and before the details are reported in the Annual Report.

At the end of a reporting period, any changes that have been implemented in the previous year are included together in a single notification to the agency.

CBE-0: Changes Being Effected 0

Changes classified as CBE-0 are minor (albeit moderate) changes to the product which can be implemented from when the FDA receives the supplemental new drug application (sNDA) application.

The product can also be distributed when the supplemental new drug application (sNDA) is received and CBE-0 changes are considered approved six months after receipt, if there are no technical issues raised by the FDA.

However, if the change is not approved then distribution must cease and a product recall may be required.

CBE-30: Changes Being Effected 30

Changes classified as CBE-30 are also deemed as minor (albeit moderate) and  Changes in this classification can be implemented and product distributed at risk, 30 days after the FDA receives the supplemental new drug application (sNDA), unless the FDA notifies the applicant otherwise.

Approval should be completed after six months, however, if the submission is rejected, a recall may also be required.

PAS: Prior Approval Supplements

This category covers major changes that are considered to have a substantial potential to adversely affect the identity, strength, quality, purity or potency of the drug product.

Product affected by these changes cannot be distributed until approval which should take up to four months, assuming there are no technical issues.

New drug Application (NDA) Vs Abbreviated New drug Application (ANDA)

What is New drug Application (NDA) :

  1. A new drug application (NDA) is a complete document that must be submitted to the U.S. Food and Drug Administration (FDA) in order to request approval for marketing a new drug in the United States.

2. Drugs for which NDAs are submitted required four phases of clinical trials and drugs that reach the NDA phase typically have a high probability of getting FDA approval.

3. NDA document must contain detailed experimental evidence (including both animal and human studies) and the document required the proposed drug’s pharmacology, toxicology, and dosage requirements as well as the intended process for manufacturing the drug. 

4. A lot of money is required for New drug Application (NDA)

5. Cost or price of drug is more in comparison to ANDA

6. Long time is required for NDA Approval.

What is Abbreviated New drug Application (ANDA) :

  1. An abbreviated new drug application (ANDA) contains data which is submitted to Food and Drug Administration (FDA)  for the review and of a generic drug product.

2. After approval the organization or company can manufacture and market the generic drug product to provide a safe, effective, lower cost alternative to the brand-name drug.

3. Generic drug applications are termed “abbreviated” because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.

4. For generic drugs bioequivalence” (which gives the rate of absorption) and bioavailability is required which can be compared to that of the innovator drug.

5. Less money is required for Abbreviated New drug Application (ANDA) in comparison to NDA.

6. Cost or price of drug is less in comparison to NDA

7. Less time is required for getting approval

European (EU) Variation Requirements

What is Variation :

Variation means any amendment to the terms of the decision granting the marketing authorization as well as any change to the summary of product characteristics and the documents forming the basis for an authorization to market a medicinal product.

European Commission has classified the variation type as   type IA/IAIN, type IB and type II.

Type IA/IAIN (do and tell) :

Changes that fall under this category are commonly referred to as “do and tell” variations because the applicant is required to implement the change and then notify the agency of the details.

This level of variation is reserved for administrative changes that are anticipated to have no impact on the quality, safety or efficacy of a product.

Variations that can be submitted as Type IA must be implemented and then the required submission made within 12 month of the implementation date.

 For changes that are categorized as Type IAIN the applicant must notify the agency within 14 days of implementation and for a single product multiples variations can be made at the same time, as long as all of them fall within the required submission deadline.

Type IB (tell, wait and do) :

Minor variations that require assessment of supporting data and are anticipated to potentially have an impact on product quality, safety or efficacy are classified as Type IB and these are also referred to as “tell, wait and do” variations.

Type IB variations are minor variations, which are neither a type IA variation, a type II variation nor an extension.

The applicant must make the submission, including all required supporting data, and await agency approval before implementing the change.

The process follows a defined assessment period of 30 days, but with agency questions it can often take up to 03 months.

Type II  :

A major change to a marketing authorization that may have a significant impact on the quality, safety or efficacy of a medicine, but does not involve a change to the active substance, its strength or the route of administration. Type II variations require a formal approval. 

They require considerable supporting documentation and must be assessed and signed off by an appropriately qualified expert in their respected field before being submitted.

Anticipated implementation time of Type II is Up to 6 months after submission.

What is Major Changes :

Where notable alterations to product registration are required, these are expected to have an impact on a product’s quality and efficacy and as such are tightly controlled, requiring in-depth assessment and review.

The Marketing authorization Holder (MAH) must demonstrate that the product will retain the same level of quality and efficacy. Comparative data is a significant requirement for such changes and must reliably show the proposed changes do not impair product quality and Assessment times for such variations are often much longer, as agencies carefully review submissions and frequently make requests for additional data and answers to questions and concerns.

What is Line Extensions:

Certain changes which affect the fundamentals of the terms of the authorization cannot be granted via a variation and are submitted as an “extension application”:

Example: changes to the active substance(s); changes to strength, pharmaceutical form and route of administration. The invented name will remain the same for the “extension”.

VariationTypeAnticipated implementation dateGuideline approval timeline
AdminType IAIN & IA14 days before implementation and up to 1 year before submissionNot applicable
MinorType IBUp to 3 months after submission30 days
MajorType IIUp to 6 months after submission60 days
Europe Variation

Packing Validation

Packing validation is performed to confirm that the resulting product from a specified packaging process consistently conforms to product attributes & requirements.

Manufacturing and packaging facility has been qualified to meet cGMP requirements.

Equipment’s / Instruments to be used in packing has been qualified / calibrated.

Machine feasibility studies shall be performed (wherever required) with tentative parameters (based on the experience and the historical data) before running the validation batches. The process parameters confirmed during machine trials and feasibility studies shall be used as process parameters for validation batches.

Machine feasibility studies shall be initiated for new packing design or new pack introduced other than existing packs.

The Packing Validation shall be conducted on minimum three consecutive batches for  each strength of product.

During packing validation below critical variable shall be considered for packing Validation Protocol preparation but not limited.

A. Blister Packing Machine

1) Forming Temperature (Low and High forming temperature).

Why at Low and High forming temperature is required to challenge :

Low Forming Temperature could lead to insufficient depth of pockets & high temperature leads to deformation of the foil.

2) Sealing Temperature (Low and High Sealing temperature).

Why Low and High Sealing temperature Required :

Sealing of the Aluminium foil depends on the Sealing Temperature. Low Sealing Temperature leads to inadequate sealing resulting in failure of leak test. High Sealing Temperature leads to deformation of the film & adverse impact on the product.

3) Speed (Low and High speed)

Why at High and Low Speed Challenge is Required :

Machine speed determines the contact time of the foil during sealing with the sealing Plate & this has an impact on the stability of the product in the final pack. Machine also has an impact on quality of embossing

4) All blister pockets filled.    

5) Leak test.

6) Over-coding / Overprinting.

7) Cutting.

8) Knurling.

9) Print registration control.

10) Splice detector.

11) Function of base and  lidding  foil.

12) At Slow Speed and High Sealing Temperature machine shall be run and sample shall be collected and send to Quality Control for analysis to know the impact of temperature on the quality of the product.

B. Cartonator :

 1) Speed (Low and High speed).

 2) Carton formation.

 3) Challenge test of Pharmacode Carton and Leaflet.

 4) Presence of Blister and Leaflet in Carton.

 5)  Embossing or over coding of batch details on the carton.

 C. Check weigher :

1) Speed (Low and High speed).

2) Under weight and over weight of carton.

D. Bundling Machine and Shrink Wrapping :

1) Temperature (Low and High temperature).

2) Speed (Low and High speed).

E. Bottle Packing Line :

1) Speed (Low and High speed).

2) Leak test                                                                                                           

3) Correct No. of Packing component in Bottles (e.g. silica gel or desiccant, cotton).

4) Torque Value.

5) % Induction Sealing Power

6) Pharmacode Challenge test of Bottle label (As Applicable).

7) Barcode Challenge test of Bottle label (As Applicable).

8) Pharmacode Challenge test of leaflet (As Applicable).

9) Barcode Challenge test of leaflet (As Applicable).

10) Bottle without leaflet.

11) Overcoding of label.

12) Challenge test of Bottle Without label.

F. Dry syrup Packing Line :

1) Speed (Low and High speed)

2) Leak test                                                                                                                  

3) Weight Variation (Net Fill Content  of individual bottle from each head)

4) Torque Value

5) Capping and Sealing Quality of Bottles

6) Bottle without foil

7) Pharmacode Challenge test of Bottle label (As Applicable)

8) Barcode Challenge test of Bottle label (As Applicable)

9) Pharmacode Challenge test of leaflet (As Applicable)

10) Barcode Challenge test of leaflet (As Applicable)

11) Bottle without leaflet

12) Overcoding of label

13) Challenge test of Bottle Without label.

Packing validation shall be performed as per Packing validation protocol

When Packing Validation Shall be Performed:

1) The introduction new packaging equipment.

2) A Change in the packaging Specification.

3) A Change in the Primary Packing Material.

After completion of packing validation activity packing validation report shall be prepared and the results obtained has to be reported in the report.

In the Summary report we have to mention the Low and High limit for Sealing temperature, Forming temperature and speed of machine etc. & based upon the report packing master documents can be revised to include the same.

Qualification Vs Validation

Qualification and Validation are two familiar words in Pharmaceutical . Every body should know the basic things about these two so Let us know what is the difference between these two……

What is Qualification:

1. The act of planning, carrying out and recording the results of tests which is performed on equipment to confirm its working capabilities and to display that it will perform routinely as intended use and against predefined specification or Acceptance criteria which is mentioned in Supplier’s recommendation / Design specification/Manual/ Supplier’s documents / Guidelines etc.

2. Qualification shall be performed or related to Equipments, Instruments, Facility and Area before use.

3. Qualification has various stages like User Requirement specification, Factory Acceptance test (FAT), Site Acceptance test (SAT), Design Qualification, Installation qualification, Operational qualification and performance Qualification.

4. Qualification shall be performed for all New / Existing Equipment, Facility, System and Instruments by the user with the help of Manufacturer / Supplier of the equipment, instrument, system and facility or 3rd party along with designated personnel from Engineering and other team members.

5. For a manufacturing process we need personnel, equipments, Instruments, Facilities, Area, systems or software which need to qualified First and then we need to validate the process.

6.Critical and Non Critical Equipment’s, Instruments, Facility and systems re qualification shall be performed after every 1 year to 7 years from the date of Qualification.

7. One batch shall be taken for Performance Qualification in case of Qualification of manufacturing equipment

What is Validation :

1. Validation is the process of establishing documentary evidence of the consistency of any process or System & it is the collection and evaluation of data from the process design stage which establishes scientific evidence that a process is capable of consistently delivering quality product.

2. Validation shall be performed for the manufacturing Process.

3. Process validation activities categorized in three stages, such as Stage 1 as Process Design, Stage 2 as Process Qualification and Stage 3 as Continued Process Verification

4. Validation shall be perform to identify the Risk or Worst Case assessment which is involves in the process.

5. For deep study & to understand the system the process validation is required.

6. Validation shall be performed for Water system, cleaning of equipment, manufacturing process, HVAC System, analytical method, computer system and water system etc.

7. For manufacturing process validation three consecutive batches shall be taken.

8. Periodic re-validation shall be done after every five years with one batch in line with process qualification requirement.

Refer Process Validation

Qualification Vs Validation

Refer Validation and its importance

Change Control Vs Deviation

Change control and Deviation are two familiar words in Pharmaceutical and both are the parts of Quality Management System (QMS). Every body should know the basic things about these two so Let us know what is the difference between these two……

What is Change control :

1. Any planned permanent or temporary departure or modification or addition or deletion from an approved/qualified process/policy/document/system/material/method/equipment etc. is called as change and the document which is required to capture all the activities is called change control.

2. Change control can be  Permanent or Temporary.

3. Change control is of two types Major and Minor.

4. Example of Change control are Change in Batch size, Manufacturing process, Formulation, Artwork related changes,  Change in raw materials, packing materials, Change in documents like Specification, Standard test Procedure and  Standard Operating procedure etc.

5. Change control can be raised before initiating any change either Permanent or temporary.

6.Change control can be closed within 90 days after approval and if required extension shall be taken.

7.Trending of the Change control shall be done on Quarterly basis.

8. The initiator who want to change in approved procedure or document has to raise change control.

What is Deviation :

1. Any unwanted event that represents a departure from approved processes or procedures or instruction or specification or established standard or from what is required. Deviations can occur during manufacturing, packing, sampling and testing of drug products.

2. Deviation  can be Planned or Unplanned

3. Deviation  is of three types Minor, Major and Critical

4. Example of deviation are Temperature and RH of area goes out of limit during manufacturing, Typographical error observed in approved documents, Standard operating procedure not followed, Breakdown of equipment, Spillage of material during unloading, Instrument calibration results goes out of limit etc.

5. Deviation shall be raised within 24 hours of the occurrence (An Incident or event)

6. Deviation can be closed or investigation of deviation shall be closed within 30 days and if required extension can be taken.

7. Similar types of deviation reported earlier should be reviewed in order to check its recurrence.

8. From deviation root cause CAPA shall be raised and if required change control can be initiated.

9. Trending of the Deviation shall be done on Quarterly basis.

10. The person or the department identifying the occurrence of deviation has to raise deviation.

For Change control procedure Refer

For Deviation Procedure refer

Dissolution Test Procedure

What is Dissolution:

Dissolution is the process by which a solid substance enters into a liquid   known as dissolution medium or solvent to form a solution.

Dissolution is a test which is used for a pharmaceutical product to evaluate the rate of release of a drug substance from the dosage form.

Dissolution test is performed for the Dosage form like Tablets, Capsules, Granules, Ointment and Creams etc. to check the percentage of drug release.

Drug dissolution in Body:

In the body, a pharmaceutical active ingredient must be in solution before it can be absorbed by the blood and ultimately carried to the receptor site to render a therapeutic effect.

Solid oral dosage forms typically begin to disintegrate and dissolve in the stomach and then the resulting solution passes into the small intestine where dissolution continues.

The dissolved active ingredient is absorbed into the blood stream through the walls of the small intestine.

Types of Dissolution Apparatus :

USP Dissolution Apparatus 1 – Basket

USP Dissolution Apparatus 2 – Paddle

USP Dissolution Apparatus 3 – Reciprocating Cylinder

USP Dissolution Apparatus 4 – Flow-Through Cell

Apparatus 1 Basket type
Apparatus 2 Paddle type

Dissolution Procedure :

The general procedure for a    dissolution   involves a liquid known as Dissolution Medium which is placed in the vessels of a dissolution unit. The medium can range from degassed or sonicated   deionized water to pH adjusted chemically-prepared solutions and mediums that are prepared with surfactants. The dissolution medium should be water or water-based having a pH in the range of 5-7 at 37 ºC and medium to be used as per the product which is written in the standard test procedure of the respective product.

Degassing the dissolution medium through sonication or other means is important since the presence of dissolved gases may affect results so the drug is placed within the medium in the vessels after it has reached sufficient temperature and then the dissolution apparatus is operated.

Sample solutions collected from dissolution testing are commonly analyzed by HPLC and Ultra violet visible spectroscopy.

There are criteria known as release specifications   that samples tested must meet statistically, both as individual values and as average of the whole and one such criteria is the parameter “Q”, which is a percentage value denoting the quantity of dissolved active ingredient within the monograph of a sample solution.

If the initial sample analysis,  known as S1 or stage 1 testing fails to meet the acceptable value for Q, then additional testing known as stage 2 and 3 testing is required. S3 testing is performed only if S2 testing still fails the Q parameter. If there is a deviation from the acceptable Q values at S3, then an OOS (Out of Specification) investigation is generally initiated.

Change Control Procedure

What is Change Control:

Any planned permanent or temporary departure or modification or addition or deletion from an approved/qualified process/policy/document/system/material/method/equipment etc. is called as change and the document which is required to capture all the activities is called change control.

Change control can be Permanent or Temporary.

What is Change control Procedure:

A formal system by which qualified persons or Subject matter Expert of different departments review proposed or actual changes that might affect a validated status of facilities, system, equipment, Document or processes.

When Change control has to taken :

Change control has to taken for the following criteria mentioned below (But not Limited to)

  • Change in Manufacturing process;
  • Change in Product formulation;
  • Change in HVAC systems / Air handling systems / air filtration systems;
  • Change in Batch / lot size;
  • Change in Manufacturing, packaging and analytical equipment;
  • Change in Facilities & Utilities;
  • Change in Raw Materials, Intermediates, Packaging materials;
  • Change in Analytical testing methods & specification,
  • Change in Water systems;
  • Change in Manufacturing Site;
  • Change in Stability (shelf life, retest period, storage and transport conditions);
  • Change in Pharmacopoeia or existing monograph
  • Artwork related changes
  • Changes in Computer Systems and Software.
  • Addition, deletion of new equipment or new product.
  • Changes in Batch documents (BMR and BPR)
  • Changes in Standard Operating Procedure (SOP)
  • Changes in Calibration schedule and Preventive Maintenance for all instruments

Flow Chart of Change Control :

CCF Flow Chart

Step wise Procedure of Change Control:

The initiator shall fill the required details in change control form with Current status, proposed change, appropriate reason or justification for change, Assessment of the change and the risk analysis.

The Justification of change shall be described in sufficient details so that reviewers and approvers clearly understand the rationale and need for the change. If required supporting data to be attached for justification.

In the risk analysis stage wherever applicable Quality risk assessment report shall be prepared during change evaluation. e.g. New product introduction at site and change in alternate source of API etc)

The Department Head of initiator department shall review the change control form along with all supportive data and supportive information.

Upon satisfactory review from Department Head; the change control form shall be submitted to change control coordinator in Quality assurance department of respective site.

The change control coordinator shall review the change control form filled by the initiator & enclosed documents for correctness & completeness. The change control coordinator shall also review the risk assessment provided for the change, if acceptable shall proceed for next stage.

The change control coordinator shall select the reviewer departments for impact assessment and comments and based on the details provided, change control coordinator shall categorize the change control as major and minor.

What is Major Change: Any change in the product, production process, quality controls, equipment, facilities, or responsible personnel that have a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. E.g. Addition/ / deletion of New API source or change in existing API source, Introduction of New Product at site and Change in Manufacturing Formula/ Manufacturing Process/ Batch Size.

What is Minor Change: Any Changes in the product, production process, quality controls, equipment, facilities, or responsible personnel that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness. E.g. Change in format or document and change in Standard Operating procedure and editorial changes etc.

Change control coordinator shall allocate a unique serial number to the change control form and update the same in change Control log Book as well as in Excel Sheet.

After completion of impact assessment and categorization (like minor & Major), the change control form shall be returned to the initiator and Initiator shall circulate the form to concerned departments for their assessment of the proposed changes.

The change control form shall also be forwarded to the Regulatory affairs department for the impact assessment over the submission/filing as per requirement. (Pl note that all change controls shall not required Regulatory affairs impact assessment)

The change control form shall also be forwarded to the customer or Qualified Person (QP) for Approval and the scan copies or e-mails or other correspondence received from Regulatory and Customer shall be archived with original change control form. (Pl note that all change controls shall not required customer/QP Approval or notification)

Comments from other departments and Marketing Authorization holder/Qualified Person/SME (Subject matter expert) shall be reviewed for its relevance prior to approval of the change control.

Then the change control coordinator shall forward the change control form to Head-QA for final approval and Head-QA/ Authorized designee shall approve the Change control form.

After approval from Head-QA, Head Corporate Quality Assurance (in case of major change controls), the change control form shall be circulated to the concerned person as scan copy.

If any change control form is rejected, then the same shall be informed to the initiator and recorded in Change control log and the change control form shall be retained by QA. The number allotted to change control form shall not be reused for next change control form and next number shall be continued accordingly.

After approval of change control form, initiator shall follow a step wise action plan for implementation of the proposed changes.

Initiator shall ensure the timely completion of all tasks stated in action plan (Section 5) and If the task stated in action plan is not completed within the target completion date, then initiator shall submit the change control extension form

Upon completion of all activities stated in action plan, initiator shall send the duly filled change control form along with all attachments to QA for review and closure and the change control coordinator shall review the change control form along with all attachments for completeness and correctness and ensure that all necessary actions are completed.

Upon satisfactory review of QA, Change control form shall be closed and same shall be updated in change control log as well as in Excel sheet.

The follow-up status of the open changes shall be tracked on the Monthly basis by QA.

All change control forms shall be closed within 90 days from the final approval or as per target completion dates mentioned in section 5 of change control form and shall be retained perpetually in the custody of quality assurance.

Change control management system timelines shall not be applicable for change controls raised for introduction of new product at site.

Change Control Form

41 Pharmaceutical Quality Control Interview Questions & Answers

Below are some Interview Questions and answers which can help the freshers as well as experience personnel for interview preparation so please Read and share if you think it useful.

1. What is Quality Control :

The term quality control refers to the sum of all procedures undertaken to ensure the identity and purity of a particular pharmaceutical product. It involves in chemical, physical and some time microbiological testing of a pharmaceutical product.

Quality control involves testing of pharmaceutical products against the specifications.

The other responsibilities of Quality Control are sampling of Raw & packing material, Testing of raw material, packing material, In process, Finished product& Stability batches, Sampling & testing of water, Calibration of Instruments, Preparation of Specification of Raw, Packing, In process & Finished products, Preparation of Standard Test procedure of Raw, Packing, In process & Finished products and reporting of result after analysis & preparation of COA.

2. What is Disintegration Test :

It is the time required for the Tablet / Capsule to break into particles, the disintegration test is a measure of the time required under a given set of conditions (Temperature) for a group of tablets/capsules to disintegrate into particles.

Cycle of shaft holding the tube basket limit is 29-32 cycles per minutes and distance covered by shaft basket is 50-60 mm and beaker temperature is 35 to 39 º C.

Disintegration is to be Performed to determine whether tablets or capsules disintegrate within the prescribed time when placed in a liquid medium at the experimental conditions.

3. What are the Disintegration Time of tablets :

  • Uncoated Tablet 15 min as per BP
  • Uncoated Tablet 30 min as per USP
  • Sugar Coated Tablet 60 min as per BP
  • Film Coated Tablet 30 min as per BP
  • Plain Coated Tablets DT in specific medium for 30 min as per USP
  • Enteric Coated Tablets DT in  simulated gastric fluid (0.1 M HCl) for 1 hr and then in simulated intestinal fluid (Phosphate buffer 6.8 pH) until disintegrate as per USP.
  • Dispersible Tablets 3 min ( 15- 25º C ) as per BP.
  • Effervescent Tablets 1 tablet in 200 mL water  for 5 min ( 15- 25º C )
  • as per BP
  • Buccal Tablets 4 hrs as per USP.
  • Soluble Tablets 3 min ( 15- 25º C ) as per BP.
  • Chewable Tablets are not require to comply with test

4. What are the Disintegration Time of capsules:

  • Gastro resistant capsule DT 2 hrs without disk in 0.1 M HCl  and phosphate buffer pH 6.8 for further  60 min as per BP.
  • Hard and Soft gelatin capsule DT 30 min as per BP & USP.

5. What is Friability Test of Tablet & friability calculation :

Friability is defined as the percentage of weight loss of powder from the surface of the tablets due to mechanical action and the test is performed to measure the weight loss during transportation.

Friability (%)  =W1– W2/W1X100

W1 = Weight of Tablets (Initial / Before Tumbling) &
W2 = Weight of Tablets (After Tumbling or friability)

Limit : Friability (%) = Not More Than 1.0 %

Tablets with individual weight equal to or less than 650 mg then take the sample of whole corresponding to as near as 6.5 gram equivalent and tablets with individual weight more than 650 mg then take sample of 10 whole tablets to perform friability test. Tablets must be de-dusted prior to and after use.

6. What is Incident :

Any unplanned or uncontrolled event in the form of non-compliance to the designed systems or procedures at any stage of testing, and storage of drug product due to system failure or equipment breakdown or manual error.

A laboratory Incident is an event in the laboratory that occurs for two primary reasons either due to analyst error or instrument error.

7. What is Calibration:

The demonstration that a particular instrument or device produces results within specified limits  by comparison with those produced by a traceable standard over an appropriate range of  measurements.

8. What is Qualification :

The action of proving that any equipment or process work correctly and consistently and  produces the expected result. Qualification is part of, but not limited to a validation process, i.e. Installation Qualification (IQ), Operation Qualification(OQ) and Performance Qualification (PQ).

The act of planning, carrying out and recording the results of tests on equipment to confirm its capabilities and to demonstrate that it will perform consistently as intended use and against predefined specification.

9. What is Deviation:

Any unwanted event that represents a departure from approved processes or procedures or instruction or specification or established standard or from what is required. Deviations can occur during manufacturing, packing, sampling and testing of drug products.

Examples of Deviations: Temperature and RH of area goes out of limit during manufacturing, Typographical error observed in approved documents, Standard operating procedure not followed, Breakdown of equipment, Spillage of material during unloading, Instrument calibration results goes out of limit etc. Deviations are of three types Minor, Major and Critical

10. What is Change Control :

It is a Approved Procedure which is taken to change in any documents, Standard operating procedures, Specification, Process parameters and change in batch size etc. Change control is raised by user department as per requirement and finally the change control is approved by Quality assurance. Change control can be raised through software or through manually.

After Final approval of change control the changes can be made in documents  and change control can be closed after completion of required action plan which is mentioned in the Change control form.

Change controls are of two types i.e Major and Minor.

11. Corrective action & Preventive action :

Corrective action :

An action taken to eliminate the cause of the existing deviation, incident or problem in order to prevent its recurrence (occurring again).

Preventive action:

An action taken to eliminate the cause of potential deviation, incident or problem in order to prevent its occurrence (an incident or event).

12. What is Chromatography :

Chromatography is an analytical technique commonly used for separating a mixture of chemical substances into its individual components, so that the individual components can be thoroughly analyzed.

Chromatography is a laboratory technique for the separation of a mixture. The mixture is dissolved in a fluid called the mobile phase, which carries it through a structure holding another material called the stationary phase and the separation is based on differential partitioning between the mobile and stationary phases.

13. What is difference between Stationary Phase Mobile Phase:

The key difference between stationary and mobile phase is that stationary phase does not move with the sample whereas mobile phase moves with the sample. Stationary phase and mobile phase are two important terms in chromatography, which is a technique of separation and identification of the components in a mixture.

14. What is Column in Chromatography:

A Chromatography column is a device used in chromatography for the separation of chemical compounds. A chromatography column contains the stationary phase, allowing the mobile phase to pass through it. The columns are mostly made of borosilicate glass, acrylic glass or stainless steel.

15. Which gas is used in Gas Chromatography :

In GC Nitrogen, Helium and Hydrogen  are considered to be suitable carrier gases but Helium is most widely used due to safety concerns  associated with hydrogen and also the fact that nitrogen  is much less efficient.

16. What is HPLC in Chemistry :

High-performance liquid chromatography (HPLC) is a technique in analytical chemistry which is used to separate, identify, and evaluate each component in a mixture.

17. What is System suitability:

Before start of analysis of the Chromatographic system like HPLC &GC system suitability has to perform to know that the system is working properly or to know the performance.

System suitability criteria may include such factors as plate count, tailing, retention, and/or resolution and the above factors are most important as they indicate system specificity, precision, and column stability.

18. What is RT & RRT in HPLC :

The amount of time it takes for the compound to pass through the column is the retention time (RT). The relative retention time (RRT) is the comparison of the RT of one compound to another.

19. Types of HPLC Pumps :

There are 3 main types of HPLC Pumps : Reciprocating pump, Displacement (or syringe) pump and Pneumatic (or constant pressure) pump.

20. What is Trailing factors :

The tailing factor is a measure of peak tailing. It is defined as the distance from the front slope of the peak to the back slope divided by twice the distance from the center line of the peak to the front slope, with all measurements made at 5% of the maximum peak height.

21. What are the different Types of  HPLC Columns :

The different Types of HPLC Columns are Normal phase, Reverse Phase, Ion Exchange and  Size Exclusion columns.

22. What is Good Laboratory Practice (GLP) :

Good Laboratory Practice contains a set of principles that provides a framework within which laboratory studies (Activities) are planned, performed, monitored, recorded, reported and archived. GLP help assure regulatory authorities that the data submitted are a true reflection of the results obtained during the study and can therefore be confidence upon when marking risk/safety assessment.

Good Laboratory Practice contains different principles which are designed to ensure and promote consistency, quality, safety, reliability and integrity of chemicals during non-clinical and laboratory testing.

23. What is Working & Reference Standard :

A reference standard is the traceable, raw material standard (usually in crystallized form) that we dissolve and volumetrically dilute to make our working standard. The working standard is what we use to “do our work.” and this information makes it traceable and is recorded in the preparation notebook.

A reference standard is prepared for use as the standard in an assay, identification, or purity test and should have a quality appropriate for its use.

24. Why is Dissolution test Required :

Dissolution tests are performed to establish drug (Active Pharmaceutical Ingredient) release characteristics of solid oral products, such as tablets and capsules. The rationale for conducting these tests is that for a product to be therapeutically effective, the drug must be released from the product and should generally be dissolved in the fluid of the gastrointestinal (GI) tract. The API in solution form facilitates the absorption of the drug from the GI tract into the systemic (blood) circulation to reach its desired target (site of action) to exert its effect.

25. How dissolution test is Performed :

The drug is placed within the medium in the vessels after it has reached sufficient temperature and then the dissolution apparatus is operated. Sample solutions collected from dissolution testing are commonly analyzed by HPLC or Ultraviolet–visible spectroscopy.

26. What is Q Stands for in Dissolution :

‘Q’ is the amount of dissolved active ingredient specified in the monograph which is required to be released in the stated time, expressed as a percentage of labelled strength, then the batch of the tablet or capsules is acceptable, if each unit is not less than Q + 5 %.

If the initial sample analysis, known as S1 or stage 1 testing fails to meet the acceptable value for Q, then additional testing known as stage 2 and 3 testing is required. S3 testing is performed only if S2 testing fails in Q parameter. If there is a deviation from the acceptable Q values at S3, then an OOS (Out of Specification) investigation is generally initiated.

27. Which tablets are used in Calibration of dissolution Apparatus :

Non disintegrating (Salicylic Acid) and disintegrating (Prednisone) tablets are used in the calibration of dissolution test apparatus.

28. What is Gas Chromatography :

Gas Chromatography is a common type of chromatography which is used for separating and analyzing compounds that can be vaporized without decomposition. Particular uses of GC include testing the purity of a particular substance, or separating the different components of a mixture and in some situations, GC may help in identifying a compound.

In gas chromatography, the mobile phase is a carrier gas, usually an inert gas such as helium or an un reactive gas such as nitrogen.

29. What is Karl Fischer Titration:

Karl Fischer titration is a classic titration method in chemical analysis that uses coulometric or  volumetric titration to determine trace amounts of water in a sample. It was invented in 1935 by the German chemist Karl Fischer. 

30. What is KF Reaction : The Karl Fischer Titration is a titration method for measuring water content in basically all types of substances. The Karl Fischer Titration is based on an iodine / iodid reaction and the the water reacts with iodine.

The endpoint of the titration is reached when all the water is consumed and the process uses an organic base (B), sulphur dioxide, iodine and an alcohol. 

31. What is Infrared Spectroscopy :

The infrared spectrum of a sample is recorded by passing a beam of infrared light through the sample and when the frequency of the IR is the same as the vibrational frequency of a bond or collection of bonds, absorption occurs. Examination of the transmitted light reveals how much energy was absorbed at each frequency (or wavelength). This measurement can be achieved by scanning the wavelength range using a monochromator.

32. What is the use of Incubator :

An incubator is a device used to grow and maintain microbiological cultures or cell cultures. The incubator maintains optimal temperature, humidity and other conditions such as the CO2 and oxygen content of the atmosphere inside. Incubators are essential for a lot of experimental work in cell biology, microbiology and molecular biology and are used to culture bacterial  cells.

33. What is Out of Specification :

Out of Specification (OOS) means the test result that falls outside the specifications or acceptance criteria which has been specified in the official monographs or the Blend, In process, Raw material, Packing material, Stability and finished product specification.

During analysis if any OOS observed then it should be investigated to find out the root cause and required Corrective & preventive actions shall be taken to avoid the reoccurrence.

There are two phases of Investigation Laboratory investigation and production process investigation.

34. What is Out of Trend :

Out of Trend (OOT) means the test result that is within the specification limit or acceptance criteria as mentioned in the Blend, In process, Raw material, Packing material, Stability and finished product specification but outside the trend of previously tested batches.

Suppose X Product has the Specification limit 95 to 105 % & we have tested many batches of product X and the trend result shows is 98 to 102 %. Suppose X Product current result is  97.5 % so in this case it is called OOT.

35. What is Stability Study :

Stability of a pharmaceutical product means how long it can maintain its original form for the duration of the shelf life assigned to it and should comply the specification without any visible changes under the influence various environmental factors like temperature and humidity.

The pharmaceutical industry conducts this testing to develop a new product and establish the shelf-life of a product.

36. What is Bracketing in Stability Testing :

The design in which only the extremes are tested at all  time points e.g., strength, pack size, container fill etc. are tested.

Bracketing is applicable if the strength are identical or very closely related in composition (e.g. for a tablet range made with the different compression weights of similar basic granulation, or a capsule range made by filling different plug fill weight of the same basic composition in to different size capsule shells. Bracketing can be applied to different container sizes or different fills in the same container closure system).

37. What is Shelf Life :

The period of time during which a drug product, if stored correctly, is expected to comply with the specifications determined by stability studies on a number of batches of the product. The shelf life is used to establish the expiry date of each batch.

38. In stability how many conditions are there :

There are Three stability Condition Long term or Controlled Room Temperature (CRT), Accelerated and Intermediate

39. What is Significant changes in Stability Study :

At long term and intermediate condition : Failure to meet the specification is considered as significant change.

At accelerated condition : Following changes are considered as “Significant change”.

A 5% change in assay from its initial value, any degradation product exceeding its acceptance criterion. Failure to meet the acceptance criteria for appearance, physical attributes. Failure to meet the acceptance criteria for dissolution.

40. What is limit of detection (LOD) :

The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value. Several approaches for determining the detection limit are possible.

Based on visual evaluation the detection limit is determined by the analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be reliably detected.

41. What is limit of Quantification (LOQ) :

The quantification limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy. The quantification limit is a parameter of quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of impurities and/or degradation products.

Based on visual evaluation: The detection limit is determined by the analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be quantified with acceptable accuracy and precision.

Requirement of Audit Trail in Pharmaceuticals

Audit Trail Log

What is Audit Trail :

An audit trail or  audit log is a security-relevant chronological record, set of records, or destination and source of records that provide documentary evidence of the sequence of activities that have affected at any time a specific operation, procedure, or event. 

Audit trail means a secure, computer-generated, time-stamped electronic record that allows for reconstruction of the history of events relating to the creation, modification, or deletion of an electronic record.

For example, the audit trail for a high performance liquid chromatography (HPLC) run should include the user name, date/time of the run, the integration parameters used, and details of a reprocessing, if any.

Audit trail should be available in analytical instruments like High performance liquid chromatography (HPLC) , Gas chromatography (GC), Infrared Spectrophotometer, Ultra Violet Spectrophotometer, Water By KF etc.

Each industry, whether tracking records or transactions, will benefit from maintaining accurate audit logs and Audit trial is being used in other sectors like Financial, accounting, and billing records, Manufacturing design controls, Nursing medical records, Health information.

Contains of Audit Trail :

From Audit trial we can check the name of the person who has assessed the system along with date and time.

Audit trail records or log contain details that include:

  1. Date, time
  2. User ID associated with the transaction or activities
  3. Name of person
  4. access to data
  5. Original result or value and changed or modified result or data
  6. Justification or reason for change
  7. Number of Invalid attempt to log the system or instrument

Audit Trail Log shall be maintained for the life of the records which can be extremely useful in historical reporting and solving problems in the future.

When Audit trails data to be Reviewed and what to be Reviewed :

Audit trail data shall be reviewed after analysis of each steps of processing or analysis or before release of the batch and audit trial report shall be attached to the respective Analytical reports.

During review the reviewer shall review the Audit trail of testing, Instrument, Operating software and all the steps followed during the testing.

Based on risk assessment the reviewer has to identify the critical checks before batch release and any observation identified during review shall be investigated and appropriate CAPA shall be taken to know the impact on the product.

For CAPA Pl refer :

For the systems where Audit trail is not available in that case alternative procedural control like Standard operating procedure and logbook shall be checked.

Who Uses an Audit Trail :

As previously mentioned, audit trails are commonly managed by staff within the IT department, such as a security manager or network administrator. A key point to keep in mind is that any user, whether a manager, employee, end-user, legal staff, an accountant, or others who touch an electronic record, will be included in the audit trail of the record. This user may be a human who makes an update to a record or accesses a system, or it may be a system that automatically makes updates/changes, such as restarting a computer. 

Advantages of an Audit Trail :

The advantages of Audit Trial can lead to the transparency of the records for compliance, record integrity and accuracy, system protection from misuse or harm.

 The Advantages are as follows :

  • User Accountability: A user is anyone who has access to the system. Implementing audit trails promotes appropriate user behavior, which can prevent the introduction of improper use of information, and unauthorized use or modifications. In addition, the user knows that their actions are automatically recorded and tied to their unique identity.
  • Reconstruction of Events: When an investigation is or triggered, the first step to remediate a problem is knowing the “when,” the “how,” and the “what” of the event. Visibility into this information can aid in problem detection and prevent future occurrences of things such as hacking, system failures, outages, or corruption of information. 
  • Violation Detection : Audit trails aid in identifying suspicious behavior or actions. Unauthorized access is a serious problem for most systems. Many regulations now have mandates for the security of information and maintaining confidentiality.
  • Other Problem Identification: Through real-time monitoring, you can use automated audit logs to identify problems that indicate system implementation issues, operational issues, unusual or suspicious activities, or system and operator errors. 

Conclusion :

FDA has issued many warning letters to the organization relating to audit trails which are reviewed during inspection so before release of any product or batch audit trails log shall be reviewed .

Limited access shall be provided to the system to avoid any problem.

Regular back up shall be taken for the system and can be saved in secured folder by the Information Technology person.