User requirement specification (URS) is a list of all the requirements from the user, like equipment to be purchased. After the preparation of the list, the documents are sent to the manufacturer to get the required materials as per the given criteria.
The user department will raise the indent for his requirement regarding machine equipment or software. He/She will give all the requirements in the format of URS, which include the functional and technical specifications for the machine equipment or software. This specification in the written format is defined as URS. It shall be very specific.
There should not be any confusion during the preparation for approval. Functional as well as technical aspects shall be clearly mentioned. The number of spare change parts required shall be mentioned in URS.
Users should also give the details of other areas which are going to affect if the machine is procured or which are the other areas that need to modify such as the environmental (AHU) control system. Also, keep in mind whether this modification is possible and feasible; is it going to impact the other existing system. URS is a supporting document for the preparation of design qualifications.
User requirement specification for equipment.
The following point must be included in URS:
- Name of the user department
- machine/equipment/software name
- Purpose of the machine/equipment/software
- Other areas of impact (AHU, movement, and space)
- Parameters to be considered for the URS.
- Model making Name with specification, and quantity with the remark.
- Capacity: give the detailed specification and quantity likes requirement in Kilogram or liters.
- The material of construction: give details about the material of construction like Stainless steel and its grades.
- Give details about Instruments on machine likes Metal detector, Camera inspection system, and pinhole detector, etc.
- Required calibration details with the specification with remarks
- Details specification: baffles, Dia, punches, Guide track, cutter, and channel.
- Specified details about required tools
- Documentation like Qualification/ manuals
- Environmental: (Include the temperature and humidity of the area ) / health safety requirements (like MCB and safety Guard) and Control (Specify needs of equipment, interfaces, output forms (e.g., USB)
- Critical control points
- Utilities. Utilities. Define the kind of power supply to use for the equipment, the requirement of UPS, or other utility requirements. Include water system, quality, or compressed gas, if required.
- Availability. Limitation of operation time for the equipment
- Supporting Documents. Operating manuals, warranty, parts, spare parts, circuit diagrams.
- User requirement specification document Shall be signed by an authorized person in the column prepared by, reviewed by, and approved by. In the end, review, revise, and approve the URS. The next step is the design qualification.
Conclusion : When a system is being created, User Requirements Specifications are a valuable tool for ensuring the system will do what users need it to try to do.
This chapter defines the requirements for good documentation practices which build a basic foundation for a good quality management system. Good documentation practices are those measures that collectively and individually ensure documentation, whether paper or electronic, is secure, attributable, legible, traceable, permanent, contemporaneously recorded, original, and accurate.
Good documentation practices follow to protect the integrity and quality of all documents/records, electronic and handwritten, used in different GMP operations and activities and ensures these records are truthful, readily retrievable and traceable.
General Requirements for GMP Documentation :
This chapter covers different levels and types of GMP documentation, including paper and
electronic records related to manufacturing, testing, packing of pharmaceutical products, APIs,
excipients, dietary supplements, food ingredients and medical devices.
These documents and records consist of raw data, reports, protocols, procedures, deviations, investigations, batch records, formats, and records related to trainings, equipments and retention for manufacturing and analytical controls.
Data integrity should always be given utmost importance which means the extent to which all data is complete, consistent and accurate throughout the data life cycle. Controls should be in place and any data integrity incident, if noticed; an appropriate corrective action should be taken to prevent recurrence of the same. Attempts to cover-up mistakes are considered as ‘data integrity’ issues and should be prohibited at all levels.
Personnel should be kept up to date about the application of good documentation practices (GDP) to ensure that the principles of ALCOA and ALCOA-plus are understood and applied to electronic data in the same manner that has historically been applied to paper records. Good documentation requirements for manual and electronic records include the following, as applicable;
A commonly used acronym that all records and data should be attributable, legible, contemporaneous, original and accurate.
A commonly used acronym for “attributable, legible, contemporaneous, original and accurate” data, which puts additional emphasis on the attributes of being complete, consistent, enduring and available – implicit basic ALCOA principles.
Attributable means information is captured in the record so that it is uniquely identified as executed by the originator of the data (e.g. a person or a computer system). Original data and further amendment if any should be traceable with respect to person, date and time, reason with signatures and in summary audit trails.
The terms legible refers to the requirements that data is clear, easily understandable, and free from overwriting and unauthorized changes, and allow a clear picture of the sequencing of steps or events in the record so that all activities conducted can be fully reconstructed by the people reviewing these records at any point during the records retention period set.
Data should be recorded concurrently at the time of performing the activity and recordings such as in-process, environmental should maintain as and when an activity is carried out along with signatures, date and time.
Data should be recorded originally, not entered on a piece of rough paper and then copied, no trial injections. OOS results should be reported immediately and data should not be newly created or rewritten after corrections and cancellations.
The term “accurate” means data should be correct, truthful, complete, valid and reliable. Data should not be falsified and fabricated.
Laboratory Records :
System must have a collection of technological & procedural controls to protect data within the system to ensure that all records are authentic, incompatible and (where applicable) confidential. In lab situation this include lab results used to determine quality, safety, strength, efficacy or purity and in manufacturing this includes all decisions related to product release and product quality.
Controls should be in place, needed for the identification, storage, protection, back-up, archive, retrieval, retention time, and disposal and to protect the integrity of its records.
Access to these records should be consistent with confidentiality and records should be readily available.
All Technical activities should be carried out with valid, correct and current effective versions of instruction documents and recording formats should have an identification number and a version number (where appropriate), allowing the sufficient space to record entries etc.
Original observations, data, and calculations should be recorded at the time of activity performed, without any bias or prejudice. These records also include the identity of personnel responsible for the performance of activity.
Automated data capture or printers should be attached and connected to equipment, such as balances, to ensure independent and timely recording of the data. User access rights to automated systems should be restricted to prevent data amendments (or audit trail).
Ability to change any clock used for recording timed events, for example, system clocks in electronic systems and process instrumentation should be restricted.
Pre-dating that is, signing for an activity in advance or post-dating (back dating that is, signing for an activity with a back-date) either documents or corrections should be strictly prohibited.
Impermanent records like data printed on thermal paper, etc. should be copied on to a permanent medium, and the copies should be attached to, or stored along with the original signed records.
All error rectifications / filling of missed entries should be traceable to the person who made
the entry, irrespective of the stage at which the error has been noticed.
All Documents / records should have page numbers (preferred format: ‘Page X of Y’). All master documents should be typed or pre-printed. Hand-written documents should not be used as master documents.
Pens with indelible ink / Ball pen(only blue colors)should be used for recording of entries and for signing off any kind of documents. All entries and records should be concise, legible, unambiguous and accurate.
Data Collection and Recording :
Good data and records management practices are critical elements of the quality system and a systematic approach should be implemented to provide a high level of assurance that throughout the product life cycle, all GMP records and data are complete and reliable.
Laboratory information management system(s) (LIMS) includes the management of data and information contained in both computerized and non-computerized systems should be well defined in quality standard procedures.
The computerized laboratory information management system used for the collection, processing, reporting, storage, retrieval of data should be validated for functionality before introduction and any subsequent changes should be validated before implementation.
Technical records of original observations, derived data and enough information to establish an audit trail, calibration records, staff records and a copy of each CoA should be retained for a defined period as applicable.
Amendments to technical records should be traceable to previous versions or to original observations. Both the original and amended data and files should be retained including the date of alteration, an indication of the altered aspects and the personnel responsible for the alterations.
Handwritten records should be signed or initialed and dated at the time the information is entered. All entries related to analysis being performed should be done in chronological order. In case continuous pages of a notebook are not being used to record data, continuity should be denoted by mentioning the reference of the notebook number or page numbers at appropriate places. For example, if experiment is recorded in a laboratory notebook on Page 25 and calculations are recorded on Page 35, cross reference of the same should be given on both pages.
All Instruction documents should have the effective date printed or stamped on them. All dates should be expressed in a format that clearly indicates the day, month and year. Time should be preferably recorded in the 24 hrs format as HH:MM. In case, date and time is printed from a machine or a computer, the date and time format of the instrument/machine should be followed and reviewed periodically for any discrepancy.
Blank spaces or pages should have a single slanting line from start to end with a signature and date and the reason for the page being blank (e.g. ‘Not Applicable’ or ‘NA’ or N/A).
If any column or row or cell is Not applicable, “NA” or N/A” should be entered in the space provided in the format.
Only validated excel sheets should be used for calculations. Wherever such excel sheets are not available, calculations should be re-verified with validated calculators. In case of analysis, step-by-step details of the testing procedure, dilutions, critical test parameters, etc. as required by the standard procedures should be documented concurrently in Analytical Raw data sheet and laboratory Logbooks. All printouts, chromatograms, spectrum, records of analysis, etc. should be duly signed with date by the activity doer person, immediately after the activity is performed.
All invalidated/disregarded Chromatograms should have a justification written by the ‘Doer’ with signatures and approved by in- charge.
Decimals less than one should be preceded by a Zero. Rounding Off’ of numerical values during analysis should be followed as under calculation of results in general notices. In case readings or values are to be recorded from digital electronic displays, same values or readings should be transcribed from system to documents.
Processing of chromatograms in chromatographic analysis should be done within 24 hours of completion of analysis sample set, with exception allowed in case of holiday. If the concerned analyst is unable to attend duty on the next working day, the task should be allocated to another analyst for processing of the chromatogram. However, in any rare case after processing of chromatogram the printout is not being taken within 24 hrs it may be taken within next 24 hrs after approval and proper reasoning.
Data Reviewing and Reporting :
Specimen signatures, initials record of each employee involved in GMP documentation should be maintained to use for traceability of signatures for all the records. Signatures essentially mean that the signatory is responsible for the accuracy of data and information for the activity being signed for. Hence, the signatory should confirm the accuracy and completeness of information and data before signing.
All GMP records should be appropriately reviewed and signature by a second person to confirm the accuracy, compliance and completeness of the work done.
A single person should not sign for multiple roles for the same activity or entry. e.g. A doer cannot be the ‘Verifier’ / ‘Reviewer’ / ‘Approver’ for the same activity or entry recorded. No employee is authorized to sign for an activity performed by another employee.
Persons preparing, reviewing or approving documents or persons recording, verifying or approving records should be on the basis of SOPs as accountability steps for different levels of review. All document signatories should be adequately trained for the activity performed by them.
Attachments to a document should have reference of the parent document, and the parent
document should have details of the attachments. In case of electronic records, all child records of a parent document should have an indication of the relationship with the parent document. Data should be recorded directly on only approved and authorized formats (e.g. Logbooks, Raw Data Sheets and other similar records). Analysis data documentation should not be recorded on unauthorized documents e.g. scrap papers, note pads, rough register and other similar items.
In case a sample has been analyzed by two or more analysts for different tests, each analyst should complete the test & related documentation for respective tests and sign (with date) his or her part. The analyst to whom the sample was issued originally should preferably sign (with date) the CoA; if this is not possible, another suitable analyst or department In charge should prepare & sign the CoA and submit it to a Reviewer. The reviewer should ensure that all tests as per specification have been carried out as per
applicable testing procedures and results are documented.
Analytical results for specific batch of a sample are compiled in the form of ‘Certificate of Analysis’(CoA), should be approved by an authorized representative. The test results should be reported accurately, clearly, unambiguously and objectively, and include all the information necessary for the interpretation of the test results, method used and sections applicable as per regulatory requirements.
Rectification of Errors / Handling of Missed Entries :
Entries in documents / records should not be cancelled, erased, obliterated or otherwise rendered illegible ,by using correction fluid/tape, overwriting, crossing out with multiple strokes, etc.
When a correction is necessary, the erroneous entry should be crossed out with a single horizontal line. Enter the correct information as close as possible to original entry that does not obscure the original entry. A brief reason for the correction must be noted as to why the change was made and the correction should be signed and dated. If sufficient space is not available to put the remark, then an annotation mark may be put near the incorrect entry and the annotation mark should be explained on the same page along with signature & date.
While stamping on documents for effective date or during review retrospectively, if it is discovered that an incorrect stamp has been used, the scenario should be handled in proper way. The error should be corrected by putting correct stamp imprint adjacent to the incorrect one. The incorrect stamp imprint should be struck off by ‘Doer’ with single horizontal line in a manner that it should be readable and not obscured. The ‘Doer’ should sign with date near the struck off, incorrect stamp imprint; this activity should be verified and signed (with date) by reviewer.
Types of Other GMP Documents :
Good data and records management practices are required to establish, implement and maintain an appropriate quality management system, the details of which should be documented in a format, such as a quality manual. The quality manual, or equivalent documentation, should include a quality policy statement of management’s commitment to an effective quality management system and to good professional practice. These policies should include a code of ethics and code of proper conduct to assure the reliability and completeness of data.
All equipments related to manufacturing, testing, and packing of pharmaceutical products, APIs, finish products should be maintained and qualified for its intended use.
Activities such as equipment qualification, analytical method validation, cleaning validation, stability study manufacturing process validation, analytical method or manufacturing technology transfers etc. should be executed on the basis of predefined , preapproved protocols and results of these activities should be documented in a final report with conclusions.
Standard operating and test procedures should be clear and concise to provide directions to trained personnel regarding a given set of activities.
A policy for retention and archiving of all records should be established. The length of time depends on the regulatory requirements or company policies consistent with its contractual obligations; however it should be 1 year after the batch expiration date.
Health Products and Food Branch Inspectorate Cleaning Validation Guideline- Health Canada.
Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products.
Types of contaminants
- Chemical – Residues of the previous product
- Biological – Microorganisms
- Physical – Particulate matter
Solubility of API shall be mentioned as per following Table:
|Solubility||Approximate volume of solvent in milliliters per gram of solute|
|Very soluble||Less than 1 part (< 1)|
|Freely soluble||From 1 to 10 parts (1 : 10)|
|Soluble||From 10 to 30 parts (10 : 30)|
|Sparingly soluble||From 30 to 100 parts (30 : 100)|
|Slightly soluble||From 100 to 1000 parts (100 : 1000)|
|Very slightly soluble||From 1000 to 10000 parts (1000 : 10000)|
|Practically insoluble||More than 10000 parts (> 10000)|
LD50 of API shall be mentioned as per following Table:
|Probable oral Lethal dose for humans (Mg/ kg)||Included descriptive terms|
|>15000||Practically non toxic|
Cleanability of API shall be mentioned as per following Table:
|Solubility||Approximate volume of solvent in milliliters per gram of solute||Cleanability Index|
|Very soluble||Less than 1 part (< 1)||Easily cleanable|
|Freely soluble||From 1 to 10 parts (1 : 10)||Easily cleanable|
|Soluble||From 10 to 30 parts (10 : 30)||Easily cleanable|
|Sparingly soluble||From 30 to 100 parts (30 : 100)||Hard to clean|
|Slightly soluble||From 100 to 1000 parts|
(100 : 1000)
|Hard to clean|
|From 1000 to 10000 parts|
(1000 : 10000)
|Mechanical water forced required|
|More than 10000 parts (> 10000)||Mechanical water forced required|
All equipments parts shall be identified as per rational criteria and categories as per bellow
- Hard to clean
- Direct contact with product
- No direct contact with product
Sampling Techniques :
Visual Inspection (Method For Validation of Cleaning of Equipments):
After cleaning of the equipment visual inspection shall be done using a torch held inclined to the surface being inspected, and a mirror (attached to stainless steel rod) to inspect the surface of equipment. Visual inspection shall be done by unaided naked eye.
For visual cleaning;
Verify the cleanliness of the product contact surfaces. Verify the cleanliness of hard to clean areas.
Verify all the product contact dismantled parts before and after assembling.
Surface Swab Sampling:
The direct Sampling technique is also commonly referred to as “Direct Surface Sampling” method. This is done by Swabbing Technique using Swabs. The direct surface sampling method is the preferred technique.
Surface sampling is identified as a sampling method considering the design, size and number of equipment.
After the completion of equipment cleaning, visual inspection shall be done.
In case, the surface of equipment is difficult to inspect, a mirror attached to a stick shall be used to inspect the cleanliness of equipment.
Complete product contact surface area shall be sampled for critical hard to clean area/ critical accessories like spray gun, punch, dies, and butter fly valve etc.
Swab Sampling for Chemical analysis:
After visual inspection is found satisfactory swab sampling shall be carried out. Wear hand gloves and nose mask before commencing swab sampling.
The swab must be wetted in purified water or suitable diluents.
Swab area shall be measured with the help of template for swabbing and the area must be 5cm x 5cm or as per protocol.
Swabbing shall be done by parallel horizontal and then tilt the swab and do vertical strokes as described below to assure that the entire area is swabbed.
After swabbing, place the swab into a stoppered test tube, wrap with aluminum foil and label the test tube for identification of swab sample.
Swab samples must be collected from different areas of equipment as stated in the cleaning validation protocol.
Send the stoppered test tube with swab to Quality Control Laboratory for analysis.
Swab sampling for Microbial analysis:
Wear sterile hand gloves and nose mask before commencing swab sampling to avoid the microbiological contamination. Sterile cotton swab shall be used for swabbing.
The sterile cotton swab shall be soaked in sterile saline.
Swabbing shall be done by parallel horizontal and then tilt the swab and do vertical strokes as described below to assure that the entire area is swabbed.
Swab area shall be measured for swabbing and the area must be 5cm x 6cm.
Microbial swab sample shall be collected before chemical swab.
Swabbing shall be done on the surface of equipments and the area is different from the area of swab taken for chemical analysis.
After swabbing, place the swab into a sterilized stoppered test tube and label the test tube for identification of swab sample.
Swab samples must be collected from different areas of equipment as stated in the cleaning validation protocol.
Send the sterile stoppered test tube with swab to Quality Control – Microbiology Laboratory for analysis.
Rinse Sampling Procedure:
After visual inspection is found satisfactory, the equipment shall be rinsed with the volume of rinsing solvent (purified water) as described in respective cleaning validation protocol (rinse sample shall be performed whenever necessary).
Rinse sample shall be collected in the bottles used for the collection of routine purified water samples.
After the collection of rinse sample, (stopper) close the bottle and label it for identification of rinse sample. Send the rinse sample bottle to Quality Control Laboratory for analysis.
Product Container Lid for Example
Method of analysis:
Methods of analysis used for determination of possible contaminant residues must be specific and sensitive.
The selection of analytical methods shall be validated for at least below mentioned parameters based on at least the following but not limited to;
- Linearity and Range,
- Limit of Detection,
- Limit of Quantification,
- Stability of solutions,
- Recovery from Equipment Surface.
FOR WORST CASE APPROACH;
10 PPM Criteria:
MACO =[Mac10] x [Swab Area]/[Shared equipment surface area between products]
Mac10 = 10 ppm x Minimum Batch Size of Product ‘B’ in kg.
Dose Criteria :
Visual inspection criteria:
No quantity of residue should be visible to naked eyes on the equipment after cleaning procedures are performed (i.e. less than 100 mcg /25 cm2).
10ppm criteria: Not more than 10ppm of active pharmaceutical ingredient of previous product is permitted in next product.
Dose based criteria:
Not more than 1/1000 of minimum daily therapeutic dose of the previous product in the maximum daily dose of the next product The acceptability limits for microbiological sample shall be determined based on;
|Parameters||Limit Dirty Equipment Surfaces||Limit Cleaned Equipment Surfaces|
|Total Aerobic Microbial Count|
|NMT 1000 cfu/swab||NMT 100 cfu/ swab|
|Total Combined Yeasts and|
Molds Count (TYMC)
|Less Than 10 cfu/swab||Less Than 10 cfu/ swab|
Re-validation shall be performed in case of any change, (at least the following but not limited to)
- Introduction of a new facility, equipment, process or product.
- Change in cleaning procedure.
- Change in cleaning agent used for cleaning.
- Reduction in minimum batch size and lowest dose of the product i.e change in MACO limit.
- Major Modification in processing equipment.
- Periodic revalidation after every three years.
- Change in regulatory requirements.
Dirty Equipment Hold Time (DEHT) –
The time from the end of manufacturing till the beginning of
the cleaning process of equipment (also called things like “soiled hold time”)
The Hold Time Study of Dirty Equipments shall be carried out by keeping equipment in idle for a period of 24 hours in dirty condition. (The Maximum possible hold period under normal conditions) to evaluate microbial contamination on equipment surface and effectiveness of cleaning process.
Clean Equipment Hold Time (CEHT) –
The time from the end of equipment cleaning till subsequent use of equipment (subsequent use includes product manufacturing).
The Hold Time Study of Clean Equipments shall be carried out after completion of “Type B Cleaning”, visual inspection by keeping equipment in idle clean condition up to 72 hours to establish the expiry of cleaning in view of microbiology.
After the equipments surfaces are found visually clean, sampling and testing shall be carried out for Microbiological enumeration Tests and residual determination (chemical analysis) on the cleaned equipment surfaces at 0 hour interval, then sampling and testing shall be carried out only for Microbiological enumeration Tests at rest intervals as per the sampling plan. (i.e., after 24 hours, 48 hours and 72 hours).
Dirty Equipment Hold Time Period : 24 Hours
Cleaned Equipment Hold Time Period : 48 Hours
What is stability studies
The ability of a pharmaceutical product to retain its physical and chemical properties within specified limits throughout its shelf life.
Types of Stability Studies :
Long term testing
Stability studies under the recommended storage condition for the re-test period or shelf life proposed (or approved) for labeling.
Studies conducted at 30°C/65% RH and designed to moderately increase the rate of chemical degradation or physical changes for a drug substance or drug product intended to be stored long term at 25°C.
Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies. Data from these studies, in addition to long term stability studies, can be used to assess longer term chemical effects at non-accelerated conditions and to evaluate the effect of short term excursions outside the label storage conditions such as might occur during shipping. Results from accelerated testing studies are not always predictive of physical changes.
Climatic zones The four zones in the world that are distinguished by their characteristic prevalent annual climatic conditions.
|Climatic Zone No.||Definition||Storage Condition||Areas covered under the zone|
|I||Temperate climate||21°C & 45% RH.||United Kingdom, Northern Europe, Canada, Russia, United states, Japan etc.|
|II||Subtropical and Mediterranean climate||25°C/60% RH||United States, Japan, Southern Europe (Portugal-Greece) etc.|
|III||Hot & dry climate||30°C/35% RH||Australia, Argentina, Egypt, Iran, Iraq, Sudan, India etc.|
|IVA||Hot & humid climate||30°C/65%||Brazil, Ghana, Indonesia, Nicaragua, Srilanka, Vietnam, Philippines, Uganda, Thailand, India etc.|
|IVB||Hot & very humid climate||30°C/75%||Brazil, Asian countries etc.|
Factors affecting stability of the product
The rate of chemical reaction increases exponentially for each 10°C increase in temperature. This relationship has been observed for nearly all drug hydrolysis and some drug oxidation reaction.
Exposure to primarily, UV illumination may cause oxidation (photo oxidation) and scission (Photolysis) of covalent bonds.
Presence of oxygen, nitrogen.
Esters & beta-lactams are the chemical bonds that are most likely to hydrolyze in the presence of water.
E.g. the acetyl ester in aspirin is hydrolyzed to acetic acid and salicylic acid in the presence of moisture, but in a dry environment the hydrolysis of aspirin is negligible.
Selection of Batches
For new drug product, samples of at least three consecutive validation batches shall be kept for accelerated, Intermediate and long-term stability.
For routine stability study, one commercial batch shall be kept for long term stability on every year.
Testing frequency shall be determined based on condition at which stability is performed.
Accelerated stability shall be conducted at 0, 3 and 6 months.
Long-term stability studies shall be carried out at the intervals of, Every three months on first year 0, 3, 6,9,12,
Every six months on second year 12, 18, 24
Every year thereafter through the proposed shelf life 24, 36, 48 and 60
Eg: 0, 3,6,9,12,18,24,36,48 and 60 months.
Intermediate stability studies (minimum four time points, including initial and final points) shall be carried out at 0,3,6,9 and 12 months or up to 60 months.
Sampling for Stability Study
QA shall inform to QC regarding type of stability study to be performed. QC shall calculate the sample quantity and shall inform to QA.
Total sample quantity per batch shall be equivalent to 1.5 times of the quantity required for single complete or partial analysis & based on number of stations plus additional one station (since stability testing has to be continued for 12 month beyond the expiry).
Incubation of Stability Samples and Storage conditions
Samples shall be incubated as per below guideline.
Identify the storage conditions based on the Pharmacopoeial data or literature information or R&D information. For add on batch use long term storage conditions.
The long term testing shall cover a minimum of 12 months’ duration on at least three validation batches at the time of submission and shall be continued for a period of time sufficient to cover the proposed shelf life.
Long term, accelerated, and, where appropriate, intermediate storage conditions for drug products are detailed in the sections below.
|Study||Storage condition||Minimum time period covered by data at submission|
|Long term||25°C ± 2°C / 60% RH ± 5% RH or 30°C ± 2°C / 65% RH ± 5% RH||12 months|
|Intermediate*||30°C ± 2°C / 65% RH ± 5% RH||6 months|
|Accelerated||40°C ± 2°C / 75% RH ± 5% RH||6 months|
* If 30°C ± 2°C / 65% RH ± 5% RH is the long-term condition, there is no intermediate condition.
If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and “significant change” occurs at any time during 6 months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria.
The initial application should include a minimum of 6 months’ data from a 12-month study at the intermediate storage condition. Temperature & Humidity of stability incubator shall be monitored on daily basis. If incubation of the stability samples is delayed by 30 days or more from the release date of the batch, initial (0 month) analysis shall be performed again before incubation.
Analysis of the sample shall be performed on the due date or if not possible, then complete within below tolerance limit from due date.
|Sr. No.||Stability Station||Tolerance (From due date of analysis)|
|1.||1M , 2M, 3M Accelerated, 3M long term, 3M Intermediate term||± 07 days|
|2.||6M Accelerated 6M, 9M, 12M long term. 6M, 9M, 12M Intermediate term.||± 15 days|
|3.||18M & onwards of long term.||± 30 days|
If there is any out of trend result or failure to meet specification (significant change) in stability analysis, results shall be intimated to Head – QC.
Head – QC or designee shall investigate the out of trend (OOT) results according to the OOT SOP .
In case of Changes in the manufacturing process or site:
If minor changes done in the manufacturing process, Sample from batches produced under each change shall be added to stability program (one batch).
If major changes done in the manufacturing process, collect the samples from the new batches (three batches) and perform the stability like new product. In such a case the protocol and report procedure number shall be changed.
In case of manufacturing site change, evaluate the affect on stability of the drug product by keeping one batch for stability.
Stability guideline :
ICH guideline: ICH Q1A (R2)
New Vendor: Manufacturer identified by Formulation Development or purchase department as a manufacturer to supply of a specific material from a specific manufacturing site.
Approved Vendor: Manufacturer of raw material, primary and printed packaging material, which has been approved by QA to supply a specific material from specific site, based on the satisfactory cGMP history as well as compliance of material to specification.
The requirement of new raw & packing materials and their profiles shall be given by the formulations development department.
In charge-purchase (Vendor development) shall identify the vendors with the available information based on specifications provided by formulations development department.
ASSESSMENT OF NEW VENDOR ( S) FOR NEW / EXISTING MATERIAL :
TEMPORARY APPROVED VENDORS
In order to select a new vendor, evaluation of the manufacturer’s capability, service performance and quality history is required. Purchase department shall collect and maintain information of the new vendor through the vendor registration form for manufacturer and for supplier or Trade.
Purchase department will get technical information regarding the material through vendor questionnaire from the vendor which includes the brief manufacturing process, TSE/BSE free declaration, impurity profile, residual solvent information, GMO free declaration, Melamine free declaration, Gluten free declaration and stability data/shelf life statement etc. as applicable depending upon the type of material.
GMO : Genetically Modified Organism
Note: For non-critical excipients requirement of impurity profile, residual solvent information, stability data, GMO/Melamine/Gluten free declarations are not mandatory.
Purchase department shall ask the vendor for analytical method and analytical method validation data for the materials claiming residual solvents. Based on the evaluation of above information and vendor registration form, Purchase/Formulation development department shall ensure that vendor is ready to supply material of required grade with specific requirement, if any.
Purchase department shall ask the vendor for pre-purchase samples of at least one batch depending upon the along with its certificate of analysis and shall be sent to Formulation Development and/or Quality Control for analysis.
Formulation Development and/or Quality Control shall evaluate the source material lots and on compliance of the sample as per specification and shall confirm the suitability as per specification to purchase department.
Formulation Development and/Quality Control will intimate the purchase and QA for suitability of sample.
Based on the assessment report from Formulation Development and/Quality Control satisfactory evaluation of data provided by the vendor, the new vendor shall be considered as a ‘Temporary Approved’.
The vendor list contains Material Code, Material Name, Synonym/ Storage Condition, Manufacturer Name and Site Address, Suppliers Name and Address and current approval status. The vendor list shall be prepared, reviewed and approved. A separate vendor list shall be prepared for US/UK market and others.
Once vendor is temporary approved, vendor code is to be assigned to the particular vendor as well as material code in SAP is to be generated by purchase department in co-ordination with SAP department.
Temporary approved” vendor becomes “Approved” vendor if following conditions are met-
Another Two commercial lots supplied by Temporary approved vendors are analysed and passed.
In case of API/ Primary packing material, vendor questionnaire is filled and vendor audit is done and complied.
In case of excipients and secondary packing material questionnaire is completed.(if required, audit to be carried out)
When manufacturing site audit is required, it shall be carried out by site QA/CQA to assess compliance with cGMP requirements.
The manufacturing site of the vendor shall be audited as per the checklist.
Based on the audit findings, a detailed report shall be classified as critical(C), Major (M) and minor (N) as described under definitions.
The purchase department shall send the site audit report prepared by site QA/CQA to the vendor. The vendor should respond in a period of 30 days after receipt of the audit report from purchase department.
The audit compliance report received from the new vendor shall be evaluated by the audit team members and recommendations shall be given to approve or reject the vendor by head QA.
Re-audit may be required for ensuring compliance in case of critical deficiencies observed during the audit.
QA shall update the vendor list once in 6 months to include or exclude approved vendor and to reflect the change in the status of vendors.
PERIODIC EVALUATION OF APPROVED VENDORS :
For approved vendor’s evaluation, following steps shall be followed:
Evaluation of the vendor’s quality performance shall be done once in a year. This annual evaluation
shall include review of rejection rate of the vendor’s lots and resolution of quality issues, if any
Yearly trending of all API from the Vendor shall be carried out of quality issues, if any.
Reassessment of quality systems shall be carried out if the rejection rate on quality grounds is higher than 20%.
All the vendor’s of API and primary packing materials shall be audited once in three years.
The vendor should respond with audit compliance report in a period of 30 days after receiving the audit report from purchase department.
If the compliance is not satisfactory, then the vendor rating will be downgraded or disapproved and deleted from the list. QA will update the vendor list accordingly and communication of the same shall be sent to QC, warehouse and purchase department.
DISQUALIFICATION OF VENDORS :
Vendors failing to meet the GMP requirements and those consistently (up to three lots) failing to meet quality standards shall be disqualified and blocked for supply of material by QA. However vendor can immediately be disqualified, Incase of any critical failure e.g. failing in potency (Assay below 80 %), microbial test (failure in pathogens). If the satisfactory corrective actions are taken by the vendor to resolve the quality problems and non- compliances, the vendor shall be re-approved for the supply.
FLOW CHART OF VENDOR APPROVAL
What is Quality Management system :
A Quality management system (QMS) is the core of any quality and compliance process. It is a regulatory requirement that the Food and Drug Administration (FDA) and other global regulatory bodies consider critical. An automated QMS system reduces audit time and findings and lowers the risk of product recalls. It improves product quality and safety, increases customer satisfaction and ensures FDA and ISO compliance.
Pharmaceutical Quality professionals are facing more challenges, and have more opportunities to improve quality and compliance than ever before. Mergers and acquisitions, complex supply chains, data integrity issues, and tightening regulations are all forces that affect pharmaceutical quality strategies and processes on a day-to-day basis. Plus, the FDA and other regulatory bodies are increasingly focused not only on compliance, but on the importance of building a culture of Quality management in the pharmaceutical industry.
An effective pharmaceutical Quality management system (QMS) will help you develop a culture of quality, support data integrity, keep suppliers under control, and maintain overall compliance. QMS data must also be structured to drive consistent metrics, risk calculations, and other trend analysis.
What is the Purpose of Quality Management system :
A Quality management system can be defined as a collection of business processes that are focused on meeting customer requirements on a consistent basis. This may seem simple enough, however, it is essential that certain obstacles are overcome for your QMS to be successful.
With this in mind, ask yourself the following questions:
- Do the same mistakes keep on being repeated?
- Is there lack of visibility between each of your departments?
- Do you have a high customer churn rate, negative customer reviews or perhaps a declining bottom line?
If you answered yes to any of the above, it may be that your QMS is not working as it should be.
The purpose of a quality management system is to ensure every time a process is performed, the same information, methods, skills and controls are used and applied in a consistent manner. If there are process issues or opportunities, this is then fed into the quality management system to ensure continuous improvement.
Importance of Quality Management System:
Here are reasons why quality management systems are so important for pharmaceutical companies:
Lessen the Risk of Errors :
The most obvious reason to invest in a QMS is to assist your company to reduce errors made when producing products. Without an advanced system where all employees involved understand their roles and responsibilities and communicate with each other, there will be more chance that errors will be made. Pharmaceutical companies of all sizes are at risk of doing mistakes without QMS in place. With an advanced QMS in place, everyone understands the tasks they need while completing a project. And, what steps ought to be taken each time to lessen the risk of errors from occurring.
Cut Costs with Quality Management System :
Errors can result in the wastage of products and money for your company. Not only are you wasting money on scraping products with errors that don’t meet the standards they require, but also you are wasting your employee’s time. Redo the work because of errors takes time far from other important tasks that still ought to be complete. As an advanced QMS, it streamlines production, makes it more efficient, and helps everyone involved become more productive. Also, companies may be able to see an increase in profits as well.
Encourage you to Constantly Upgrade :
Implementing an advanced QMS is a great place to begin, but the work doesn’t end there. The current system which you are using is unlikely to remain consistent, which is really a good thing. A quality management system encourages companies to keep them updated to improve their operations and makes it easier to identify areas where you ought to change. Technologies may also change, requiring you to adapt and upgrade your system to run more smoothly.
Customer Satisfaction :
Improving your company’s efficiency and production process are huge benefits to having an advanced QMS in place. However, the foremost important goal of all pharmaceutical companies is to make products that will help customers to live better. Ensuring that you’re producing high-quality products that are thoroughly checked over throughout the whole production process means you’re delivering better products to your customers. Customer satisfaction is more important for the companies, as they give your company positive reviews, which leads to increase sales.
Below are the responsibilities of Engineering personnel in Pharmaceutical Industry (But not limited To)
|1. To follow Good Engineering Practice.|
|2.Preparation and Review of departmental SOPs|
|3. Preparation and Review of PM schedule, checklist and attending breakdown.|
|4. Observation and Guideline in installation activities of new equipment’s or projects at site.|
|5. Implementation of SAP|
|6. To review and undertake audits of vendor quality management system.|
|7. Review and implementation of Technical Agreement.|
|8. New vendor developments for different engineering services and follow up.|
|9.To witness calibration and validation activities and review of calibration certificates.|
|10. Support in installation activities of equipment’s.|
|11. Validation and Review of Site master plan and Coordination with contract persons|
|12.Preparing all drawings and related system engineering documents, such as :|
|P & I drawings|
|Utility drawing such as HVAC, Water system|
|Building and Room Drawings|
|Equipment Component Identification|
|Identification of Calibration Requirements|
|Equipment Installation and System Construction Procedures.|
|13. Co-ordination of the calibration activities for all critical instruments as identified by the validation team.|
|14. Executing, Installation Qualification and Operational Qualification tasks and assisting in the execution of Performance Qualification.|
|15. Maintenance of process & utility equipment.|
|16. Responsible for handling of change control, deviation, and incidents within the department.|
|17. To ensure the ALCOA Data Integrity Checks.|
Annex 11 requires that audit trails are regularly reviewed to ensure data integrity. There are a significant amount of inconsistent interpretations about the requirement to regularly review audit trails. Some of the interpretations are that a periodic review of audit trails should be performed to ensure data integrity. Under a periodic review approach some companies have implemented a monthly, quarterly, bi-annual and yearly review of audit trails. The challenge is how relevant it is to perform a periodic review after an extended period of time when the data was generated. What is the value? What are we supposed to be looking for? What constitutes a data integrity issue? Which data is critical? Should we take a risk based approach?
This article will provide answers to these challenging questions and solutions about how to perform regularly audit trail reviews.
The Challenges :
Aligning with the requirement to regularly perform audit trails reviews can be very challenging for some companies. This requirement is based on the assumption that all system provide audit trails that are “user friendly”, adequate and easy to review for data integrity. One of the biggest challenges is that some systems specifically in the Quality Control laboratories don’t generate audit trails that facilitate a review regularly. Another challenge is whether to perform periodic review or to assess the audit trails prior to signing or approving the data. Can we implement the same approach for all areas with GMP impact or can we take a risk based approach. Which approaches are more value added and not just a paper work exercise?
Unfortunately Annex 11 and other data integrity philosophies fail to provide adequate guidance and direction about how to regularly review audit trails. There is always the challenge on how to deal with all the assumptions related to this requirement and this also includes resources to regularly review audit trails. In order to review audit trails regularly qualified resources are needed to perform this work. The resource impact needs to be clearly understood based on the population of impacted systems, the volume of the reviews and the defined frequency. All the potential challenges need to be well understood and addressed prior to committing to perform audit trails reviews, otherwise the effort will be meaningless and simply a paper exercise.
Audit Trail Assessments :
In order to align with the requirement to regularly review audit trails an assessment needs to be performed for all impacted systems. The audit trail assessment is the first and the most critical steps to implement audit trail reviews. An inventory of all impacted systems need to be created. This inventory will identify all impacted systems that need to be included in the audit trail assessment. The intent of the assessment is to identify whether each individual system provide audit trails that are adequate and that can be used for performing these reviews.
System level risk assessments need to be performed to identify whether the system is high, medium or low risk. The system risk needs to be used to prioritize the audit trail assessment and implementation of periodic reviews. For example a quality control system to measure critical quality attributes is probably high risk and should be a priority. A risk based approach will be discussed in more detail later in this article.
Each functional area that have GxP computer systems need to perform the audit trail assessment to determine the following:
- Who has access to view the audit trails?
- Can the audit trail be printed from the application?
- Can the reviewer select a data range?
- Can the reviewer select a specific activity of interest during the audit trail review?
- Will it feasible to include the audit trail with the data results?
- Will it be feasible for QC systems to include the audit trail with the assay results?
- Are user’s action time and date stamped?
- Does the audit trail records creation, modification and deletion of records?
The answer to each question will be potentially being different for each system assessed. Based on the results of this assessment remediation activities may be required to address any gaps or improvements need for audit trails.
To document the results of the audit trail assessment a summary report should be created to summarize the findings.
A remediation plan should be created to describe the corrective actions that will be taken for each system.
Once all remediation activities are closed procedures need to be created or revised to include the steps for performing audit trails periodic review.
Risk based Approach :
A risk based approach to audit trail reviews is critical for an implementation that provide a meaningful process without having a negative impact on cost and resources. The fact is that without taking a risk based approach audit trail reviews can have a negative impact on cost and resources. Audit trail reviews for GxP systems are a time consuming activity that requires resources to execute and manage the information an actions related to the review.
In order to take a risk based approach to audit trail reviews the system risk level need to be identified. Prioritizing the audit trail assessment based on the level of risk is critical to prioritize the assessments and implementation. Systems involved in the testing of Critical Quality Attributes are high risk and should be the highest priority during the assessments and implementation.
The system risk level should be used to establish the frequency and scope of the audit trails periodic reviews. For high risk systems such as those used in Quality Control the audit trails should be reviewed with the test results to ensure the integrity of the test data. The scope of this review should include assessing the accuracy and integrity of the data using the audit trail. In this situation the audit trail will be reviewed for the following:
- Changes to test parameters
- Changes to data processing parameters
- Data deletion
- Data modifications
- Analyst actions
- Data manipulation
- Excessive integration of chromatography peaks
- Security breaches related to data
QC procedures need to define the controls related to data integrity; this will ensure consistency during the audit trail review.
For medium and low risk systems the approach will be less intensive that for high risk. For these systems it can be possible to review periodically the audit trails. The periodic review period should be established based on the level of system risk. Medium risk systems should be reviewed more frequently than low risk systems. For example a document management system is probably medium risk that should be on a periodic review schedule of every six months or a yearly schedule. Low risk system can be reviewed on a yearly or bi-annual basis.
The scope of the audit trail reviews for medium and low risk systems should include the following:
- Data changes
- Data deletions
- Unauthorized access or transactions
To implement audit trail reviews is critical to take a risk based approach. A one size fits all approach can have a significant impact on cost and resources.
In summary a risk based approach is critical for the implementation of audit trail periodic reviews.
Once the audit trail assessment are performed, system risk identified and all corrective actions are closed the audit trail reviews can be implemented. Prior to implementation the impact to resource need to be well understood based on the expected volume of work. Once this impact is understood hiring and reassigning of resource need to be completed prior to formal implementation.
Procedure may need to be created or revised to include the approach of audit trails reviews for each system based on the results of the assessment and system risk.
The last step is training all impacted resources on the applicable procedures with an emphasis of data integrity.
Annex 11 requires that audit trails are reviewed regularly to ensure data integrity. The frequency and scope of the audit trail reviews is not defined in annex 11. Audit trails periodic reviews have impact on resources and cost. To minimize the cost and resource impact and risk based approach should be taken for the implementation of audit trails review. The approach should be based on the system risk level which will facilitate defining scope and frequency of the reviews.
An audit trail review when properly implemented can increase the integrity of data generated by GxP systems.