ANY COMMENTS OR SUGGESTIONS ABOUT HOW WE CAN IMPROVE ,PLEASE LET US KNOW:
grrao.vvm@gmail.com
____________________________________________________________________
· What is Drug Registration ?
Once a product has been given authorization for Marketing or free distribution and Entitlement such as first- track procedures, ect.
· What are Regulations / Directives?
Regulations / Directives are a form of law, sometimes referred to as subordinate legislation, which define the application and enforcement of legislation. Regulations / Directives are made under the authority of an Act, called an Enabling Act. Regulations / Directives are enacted by the body to whom the authority to make Regulations / Directives has been delegated in the Enabling Act, such as the Governor in Council or a minister, etc. Regulations are USFDA terminology. Directives are EMEA / EDQM terminology.
· What are Guidelines?
Guidelines are departmental documents that are used to interpret legislation and/or regulation. Although they may be derived from legislation and are often used to advise how one might comply with a regulation, guidelines do not have the force of law.
· What is Marketing Authorization ?
Official document issued by the competent Drug Registration Authorities for the purpose of marketing of a product after evaluation for Quality, Safety and Efficacy.
· What is Evaluation ?
Interpret the data and determine if the product has acceptable Quality, Safety and Efficacy.
European Directorate for the Quality of Medicines (EDQM) was extended to cover two more new areas, i.e., organ transplantation and blood transfusion. So the EDQM & Health Care was started from 14.12.2006 onwards.
Type A New Active Substances
Type B Existing Active Substances not included in the EP or Pharmacopoeia of an EU Member State.
Type C Pharmacopoeial Active Substances included in the EP or Pharmacopoeia of an EU Member State.
DMF holders should update their DMFs for every five years (Quinquennial Update).
Type I : Manufacturing Site, Facilities, Operating Procedures, and Personnel (no longer available)
Type II : Drug Substance, Intermediate, and Material used in their preparation or Drug Product
Type III : Packaging Material
Type IV : Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
Type V : FDA Accepted Reference Information
DMF holders should update their DMFs annually (Annual Update). FDA is in the process of sending Overdue Notification Letters (ONLs) to DMF holders that have not been updated, i.e., no amendments or annual reports in three years. If a DMF holder does not respond to this letter within 90 days, the DMF is retired and is unavailable for review. U.S. standard paper size (8-1/2 by 11 inches) is preferred for USDMF.
Some DMFs may be listed as inactive which are, in fact, still active. Every effort will be made to correct any errors. The following types of DMFs may be filed as Type V DMFs without requesting prior clearance from FDA :
Manufacturing Site, Facilities, Operating Procedures, and Personnel for sterile manufacturing plants.
Contract Facilities for the manufacture of biotech products.
- How many types of Canadian DMFs are in place ?
Type I : Active Pharmaceutical Ingredients
Type II : Packaging Materials
Type III : Colourants, Flavours, and Other additives
Type IV : Drug Products.
DMF holders should update their DMFs bi-annually (Biannual Update).
· How many types of applications for a new Certificate of Suitability
The following types of application are there for new COS :
Chemical / Chemical and Sterile / TSE / Double (Chemical and TSE) / Double and Sterile / Herbal
- What is the criteria for fixation of unknown impurity limit in API ?
As per ICH Q3A,
If maximum Daily Dose is < 2 g / day - Unknown Impurity is 0.10%
Reporting Threshold is 0.05%
Identification Threshold is 0.10% or 1.0 mg per day intake (whichever is lower)
Qualification Threshold is 0.15% or 1.0 mg per day intake (whichever is lower)
If maximum Daily Dose is > 2 g / day - Unknown Impurity is 0.05%
Reporting Threshold is 0.03%
Identification Threshold is 0.05%
Qualification Threshold is 0.05%
· What is DCP and What is MRP ?
DCP and MRP’s are EU registration procedures.
Mutual Recognition Procedure is European review procedure for products with an existing Marketing Authorizations. Only possible, if authorization has already been granted.
Decentralized Procedure is alternative review procedure. Only possible, if no authorization has already been granted.
Procedure will be done among
RMS à Reference Member State
CMS à Concerned Member State
MAH à Marketing Authorization Holder
· What is USFDA Form 2656 ?
It is Registration of Drug Establishment / Labeler Code Assignment. It is related to NDC Numbering.
· What is USFDA Form 2657 ?
It is Drug Product Listing Form. It is For NDC Number.
It is USFDA inspection intimation form. [21 working days is general intimation period]
· What is USFDA Form 483 ?
Form 483 is form to furnish USFDA inspectional observations.
· What is COPP ?
COPP is Certificate of a Pharmaceutical Product. It is an export certificates for unapproved products, that are not authorized for sale in country, which may be legally exported to foreign governments. It is recommended by WHO.
· How many types of application for revision or renewal of Certificate of Suitability ?
Simple Notification
Multiple Notifications (max 3)
Simple minor revision
Multiple minor revisions (max 3)
Simple major revision
Multiple major revisions (1 major, max 3 in total)
Consolidated revision (more than 3 changes)
Quinquennial renewal
Evaluation of sterilisation data
Notifications :
The determination of validity of a notification is completed within 2 weeks after receipt of a request.
Then either an acknowledgement of a valid notification is sent or a revised certificate is granted if necessary.
An application for multiple simultaneous notifications is possible under conditions: - maximum 3 changes.
Minor changes :
T 0 (within 5 days after receipt of the request): a letter of acknowledgement of receipt is sent to the applicant.
T 30 days: either the request is approved and a revised certificate is granted.
or
A letter of request for additional information is sent (clock-stop).
If clock-stop: the applicant is requested to submit a reply within 30 days.
Failure to submit a reply in time will lead to the rejection of the request for revision.
Again new T0 and new T 30 day’s process will start.
Major changes :
T 0 (within 5 days after receipt): a letter of acknowledgement of receipt is sent to the applicant.
T 90 days: either the request is approved and a revised certificate is granted.
or
A letter of request for additional information is sent (clock-stop).
If clock-stop: the applicant is requested to submit a reply within 30 days.
Failure to submit a reply in time will lead to the rejection of the request for revision.
Again new T0 and new T 30 day’s (except TSE certificates: 90 days) process will start.
Quinquennial renewal :
The holder of the certificate should apply for the renewal of their certificate about 6 months prior to expiry date.
T0 (within 5 days after receipt): a letter of acknowledgement of receipt is sent to the applicant.
T 120 days: either approval and a renewed certificate is sent.
or
A letter of request for additional information is sent (clock-stop).
If clock-stop: the applicant is requested to submit a reply within 30 days.
Failure to submit a reply in time will lead to the rejection of the request for revision.
Again new T0 and new T 30 day’s (except TSE certificates: 90 days) process will start.
Monographs revisions :
When a revised monograph is published, a letter is sent to the relevant holders of to update their dossier.
The holder is requested to submit the data within 90 days.
T0: At receipt of the data, start of evaluation (no letter from EDQM)
T120 days: sending of an acknowledgement of valid data.
or
A letter of request for additional information (clock-stop).
If clock-stop: the applicant is requested to submit a reply within 30 days.
Failure to submit a reply in time will lead to the rejection of the request for revision.
Again new T0 and new T 30 day’s process will start.
· What is the Structure and Content of Drug Submissions In CTD Format ?
Common Technical Document (CTD) is updated and harmonized format for Drug Master File (DMF) for registration for pharmaceuticals for human use. It is accepted by most of the regulatory agencies. Modules suggested by ICH as follows :
Module 1: Administrative Information and Prescribing Information
Module 2: Common Technical Document Summaries
Module 3: Quality
Module 4: Nonclinical Study Reports
Module 5: Clinical Study Reports
· What are the topic to be covered in CTD submission for Drug Substance ?
Module 3.2 : Body of data
1. General Information
1.1 Nomenclature
1.2 Structure
1.3 General Properties
2 Manufacture
2.1 Manufacturer(s)
2.2 Description of Manufacturing Process and Process Controls
2.3 Control of Materials
2.4 Controls of Critical Steps and Intermediates
2.5 Process Validation and/or Evaluation
2.6 Manufacturing Process Development
3 Characterisation
3.1 Elucidation of Structure and other Characteristics
3.2 Impurities
4 Control of the Drug Substance
4.1 Specification
4.2 Analytical Procedures
4.3 Validation of Analytical Procedures
4.4 Batch Analyses
4.5 Justification of Specification
5 Reference Standards or Materials
6 Container Closure System
7 Stability
7.1 Stability Summary and Conclusions
7.2 Post-approval Stability Protocol and Stability Commitment
7.3 Stability Data
Module 2.3 : Quality Overall Summary
· Which guideline is supporting to address the changes in USA ?
We can address the changes of APIs as per Post Approval Changes. BACPAC [Bulk Actives Post Approval Changes was withdrawn by USFDA on 06.01.2006. No other guideline is available from USFDA as on date.
We can address the changes of formulation related issues as per SUPAC [Scale Up & Post Approval Changes].
· Which guideline is supporting to address the changes of APIs in Europe ?
As per Guideline of request for revision or renewal of Certificate of Suitability.
How to address the variation in EU on Medicines & Health Products
?
Variation Categories:
Type IA à Minor Variations à
No Assessment
à Notification to authorities
à No assessment; no request for additional information /clarification
à Acknowledgement of validity within 14 days
à Immediate implementation
à Examples Type IA
Change in name of MAH, manufacturer
New secondary packaging site
Tightening of specification limits
Submission of new CEP from approved manufacturing
Deletion of manufacturing site
Type IB à Minor Variations à
Assessment (short assessment as in current Type I)
à Notification to authorities
à Acknowledgement of start of procedure
à Short assessment within 30 days
à No comments
à Implement
à If comments
à Extend by 30 days
à (EMEA) Positive or Negative ‘Notification’
à
Examples Type IB
Change in shelf-life
Addition of test procedure (not biologicals)
New active substance manufacturer (not biologicals)
Change in name of product
Change in primary packaging material (not biologicals)
Minor change in manufacturing process (not biologicals)
Type II à Major Variations à
Assessment
à Application to authorities
à Acknowledgement of start of procedure
à Assessment
à 60 Days TT (clock-stop + ext.)
à or
à Shorter – Urgent Changes (Safety)
à Assessment within 90 Days – indications
à Centralised Procedure : CPMP Opinion
+
Decision-making process without Standing Committee Consultation
à Extensions
à Full assessment required (up to 210 days)
à Modification or extension of the MA
à Examples Type II
New Strength
New Route of Administration
Certain changes to Active Substanc
· All changes to new indications à Type II
· What is DCGI and NPPA ?
DCGI : Drugs Controller General of India.
NPPA : National Pharmaceutical Pricing Authority [Drug Price Regulator]
· What is the general procedure for USFDA Audit ?
As per FDA Form 2438 [Effective from February 2006] .
There are two basic types of inspections :
1. Surveillance 2. Compliance
Surveillance inspections are conducted on a routine basis to satisfy FDA’s responsibilities to inspect drug-manufacturing facilities.
Compliance inspections are conducted in response to violative surveillance inspections and when a need arises to inspect a facility for-cause.
This program follows the approach in the main compliance program.
There are two alternate approaches to inspecting a facility to satisfy FDA inspection obligations :
1. Full Inspection 2. Abbreviated Inspection
A general scheme of systems for auditing the manufacture of API consists of the following:
1. Quality System 2. Facilities and Equipment System
3. Materials System 4. Production System
5. Packaging and Labeling System 6. Laboratory Control System
· What is NDC numbering system ?
National Drug Code is a unique 10-digit, 3-segment number.
1st segment is the Labeller Code. It is assigned by the FDA.
2nd segment is the Product Code. It is to be assigned by the firm with respect to identifies a specific strength, dosage form, and formulation for a particular firm.
3rd segment is the Package Code. It is also to be assigned by the firm to identifies package sizes and types.
The NDC will be in one of the following configurations: 4-4-2, 5-3-2, or 5-4-1.
Because of a conflict with the HIPAA standard of an 11 digit NDC, many programs will pad the product code or package code segments of the NDC with a leading zero instead of the asterisk. Since a zero can be a valid digit in the NDC, this can lead to confusion when trying to reconstitute the NDC back to its FDA standard.
Example: 12345-0678-09 (11 digits) could be 12345-678-09 or 12345-0678-9 depending on the firm's configuration.
By storing the segments as character data and using the * as place holders we eliminate the confusion.
In the example, FDA stores the segments as 12345-*678-09 for 5-3-2configuration or 12345-0678-*9 for 5-4-1 configuration.
· What is SMF ?
SMF (Site Master File) is a document prepared by the manufacturer containing specific and factual Good Manufacturing Practice information about the production and/or control of pharmaceutical manufacturing operations carried out at the named site.
SMF should be concisely written in English and as far as possible no exceed 25-30 A4 sheets. SMF should have edition number and effective date.
We can make the SMF as per guidelines of Schedule-M, PIC/S, HAS, MCC, ect.
· What is Patent / Trademark / Copyright ?
A PATENT for an invention is the grant of a property right to the inventor, issued by the United States Patent and Trademark Office (USPTO). Generally, the term of a new patent is 20 years from the date on which the application for the patent was filed in the United States or, in special cases, from the date an earlier related application was filed, subject to the payment of maintenance fees. U.S. patent grants are effective only within the United States, U.S. territories, and U.S. Possessions. Under certain circumstances, patent term extensions or adjustments may be available.
The right conferred by the patent grant is, in the language of the statute and of the grant itself, “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States or “importing” the invention into the United States. What is granted is not the right to make, use, offer for sale, sell or import, but the right to exclude others from making, using, offering for sale, selling or importing the invention. Once a patent is issued, the patentee must enforce the patent without aid of the USPTO.
There are three types of patents:
1) Utility patents may be granted to anyone who invents or discovers any new and useful process, machine, article of manufacture, or composition of matter, or any new and useful improvement thereof;
2) Design patents may be granted to anyone who invents a new, original, and ornamental design for an article of manufacture;
3) Plant patents may be granted to anyone who invents or discovers and asexually reproduces any distinct and new variety of plant.
A TRADEMARK is a word, name, symbol, or device that is used in trade with goods to indicate the source of the goods and to distinguish them from the goods of others.
A service mark is the same as a trademark except that it identifies and distinguishes the source of a service rather than a product.
The terms “trademark” and “mark” are commonly used to refer to both trademarks and service marks.
Trademark rights may be used to prevent others from using a confusingly similar mark, but not to prevent others from making the same goods or from selling the same goods or services under a clearly different mark.
Trademarks which are used in interstate or foreign commerce may be registered with the USPTO.
The registration procedure for trademarks and general information concerning trademarks is described on a separate page entitled “Basic Facts about Trademarks”.
A COPYRIGHT is a form of protection provided to the authors of “original works of authorship” including literary, dramatic, musical, artistic, and certain other intellectual works, both published and unpublished.
The 1976 Copyright Act generally gives the owner of copyright the exclusive right to reproduce the copyrighted work, to prepare derivative works, to distribute copies or phone records of the copyrighted work, to perform the copyrighted work publicly, or to display the copyrighted work publicly.
The copyright protects the form of expression rather than the subject matter of the writing. For example, a description of a machine could be copyrighted, but this would only prevent others from copying the description; it would not prevent others from writing a description of their own or from making and using the machine.
Copyrights are registered by the Copyright Office of the Library of Congress.
It is Indian Good Manufacturing Practices and Requirements of Premises, Plant and Equipment for Pharmaceutical Products as per Drugs and Cosmetics Act 1940.
· How many types of options for Patent Certifications ?
There are four types and options are there for patent certifications :
Paragraph I / Paragraph II / Paragraph III / Paragraph IV
Paragraph I è No Patent Filed
è 21 CFR 314.94(a)(12)(i)(A)(1)
è No patents referencing the listed drug in the Orange Book
è Firm is aware of non-listed patent
è Allows for immediate effective date of approval
è Does not mean the patent cannot be enforced
Paragraph II è Patent Has Expired
è 21 CFR 314.94(a)(12)(i)(A)(2)
è Patent listed in the Orange Book
è Cite patent number and provide expiration date
è Allows for immediate effective approval date
Paragraph III è The Patent Will Expire
è 21 CFR 314.94(a)(12)(i)(A)(3)
è Listed patent in force at time of submission of ANDA
è Cite patent number and provide expiration date
è State intentions not to market until after patent expires
è Allows for approval immediately after expiration of the listed patent
Paragraph IV è Patent Challenge - Invalidity, Non-Infringement or
è Unenforceable 21 CFR 314.94(a)(12)(i)(A)(4)
è Intent to market prior to expiration of patent
è Notification provisions apply
è 45-day clock for suit
è Allows for immediate effective date of approval if no suit brought within 45 days
è If suit brought within 45 days, no approval for 30 months or until court decision
è Possible 180-day exclusivity
· What level of testing is needed after cleaning validation?
The answer to this question depends on individual situations. Typically, companies perform visual inspection and remove rinse samples as required. A practical approach for monitoring the effectiveness of cleaning after completion of cleaning validation in an effective, scientific sound and inexpensive way is given below:
Visual inspection of the cleaned equipment. Only after this check is considered satisfactory, proceed with the next step.
Take a rinse and/or swab sample (one litre of rinsing liquid is usually required)
Determine the dry residue by evaporating about 500 ml to dryness in a small flask using a rotary evaporator. This unspecific test covers also inorganic salts, known or unknown organic products and will detect the total residues. (this test might be omitted for the drying equipment, in this instance we have a pure API or intermediate and typically no potential for side products, degradation, etc.)
If the result meets the specification, proceed to specific (chromatographic) technique. Start with a TLC-limit test (inexpensive and fast to validate, broad detection range – UV and specific derivatisation – if these techniques are combined, the method is very specific for the different impurities potentially present in the sample. Apply 2 samples: the last washing liquid (to see all potential residues), the rinsing liquid (to look for the residue) and two standards: one of the suspected residual product at a concentration that is the limit accepted, and a 1:2 dilution of the standard. If the main spot in the rinsing liquid has lower intensity than the standard, the equipment is clean. The second standard is for confirmation of detection.
If TLC is not the appropriate technique, revert to HPLC or GC.
· What is geno toxic impurity ?
According to current regulatory practice it is assumed that (in vivo) genotoxic compounds have the potential to damage DNA at any level of exposure and that such damage may lead/contribute to tumour development.
Thus for genotoxic carcinogens it is prudent to assume that there is no discernible threshold and that any level of exposure carries a risk.
However, the existence of mechanisms leading to biologically meaningful threshold effects is increasingly acknowledged also for genotoxic events.
This holds true in particular for compounds interacting with non-DNA targets and also for potential mutagens, which are rapidly detoxified before coming into contact with critical targets.
The regulatory approach to such chemicals can be based on the identification of a critical No-Observed-Effect Level (NOEL) and use of uncertainty factors.
Even for compounds which are able to react with the DNA molecule, extrapolation in a linear manner from effects in high-dose studies to very low level (human) exposure may not be justified due to several protective mechanisms operating effectively at low doses.
However, at present it is extremely difficult to experimentally prove the existence of threshold for the genotoxicity of a given mutagen.
Thus, in the absence of appropriate evidence supporting the existence of a threshold for a genotoxic compound making it difficult to define a safe dose it is necessary to adopt a concept of a level of exposure that carries an acceptable risk.
The toxicological assessment of genotoxic impurities and the determination of acceptable limits for such impurities in active substances is a difficult issue and not addressed in sufficient detail in the existing ICH Q3X guidances.
The data set usually available for genotoxic impurities is quite variable and is the main factor that dictates the process used for the assessment of acceptable limits.
In the absence of data usually needed for the application of one of the established risk assessment methods, i.e. data from carcinogenicity long-term studies or data providing evidence for a threshold mechanism of genotoxicity, implementation of a generally applicable approach as defined by the Threshold of Toxicological Concern (TTC) is proposed.
A TTC value of 1.5 µg/day intake of a genotoxic impurity is considered to be associated with an acceptable risk (excess cancer risk of <1>
From this threshold value, a permitted level in the active substance can be calculated based on the expected daily dose.
Higher limits may be justified under certain conditions such as short-term exposure periods.
The concentration limits in ppm of genotoxic impurity in drug substance derived from TTC can be calculated based on the expected daily dose to the patient using equation
TTC [mg / day] è Threshold of Toxicological Concern
Concentration Limit (ppm) = --------------------------------
Dose [g / day]
· What is MACO ?
Establish the limit for Maximum Allowable Carryover (MACO) according to the following equation.
TDD previous x MBS
MACO = ---------------------------------------
SF x TDD next
MACO Maximum Allowable Carryover: acceptable transferred amount from the investigated product ("previous")
TDD previous Standard therapeutic dose of the investigated product (in the same dosage form as TDD next)
TDD next Standard therapeutic dose of the daily dose for the next product.
MBS Minimum batch size for the next product(s) (where MACO can end up)
SF Safety factor (normally 1000 is used in calculations based on TDD)
· What is NOEL?
NOEL (No Observable Effect Level) can identify according to the following equation
LD50 (g/kg) x 70 (kg a person)
NOEL = -----------------------------------------
2000
From the NOEL, MACO can be calculated according to:
NOEL x MBS
MACO = ------------------------------
SF x TDD next
MACO :Maximum Allowable Carryover: acceptable transferred amount from the investigated product ("previous")
NOEL :No Observed Effect Level
LD50 :Lethal Dose 50 in g/kg animal.
The identification of the animal (mouse, rat etc.) and the way of entry (IV, oral etc.) is important.
70 kg :70 kg is the weight of an average adult
2000 :2000 is an empirical constant
TDDnext :Largest normal daily dose for the next product
MBS :Minimum batch size for the next product(s) (where MACO can end up)
SF :Safety factor
· What are limits for Safety factors ?
Topicals : 10 - 100
Oral Products : 100 - 1000
Parenterals : 1000 - 10 000
Remarks: API`s in development may require higher safety factors due to lack of knowledge.
· How can you Classify the Impurities ?
Organic impurities (process- and drug-related)
Inorganic impurities
Residual solvents
Polymorphic forms
Enantiomeric impurities
Organic impurities can arise during the manufacturing process and/or storage of the API. They can be identified or unidentified, volatile or non volatile
e.g.:
• Starting materials
• By-products
• Intermediates
• Degradation products
• Reagents, ligands and catalysts
Inorganic impurities can result from the manufacturing process, they are normally known and identified and include
e.g.:
• Reagents, ligands, catalysts
• Heavy metals or other residual metals
• Inorganic salts
• Other materials, e.g. filter aids, charcoal….
Class I : Solvents to be avoided
Benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene, 1,1,1- trichloroethane
Class II : Solvents to be limited
Acetonitrile, Chloroform, Cyclohexane, Dioxane, Methanol, Methylbutylketone, Tetrahydrofurane, Toluene, …...
Class III : Solvents with low toxic potential
Acetone, Butanol, Butyl acetate, DMSO, Ethanol, Ethyl acetate, Ethyl ether, Heptane, Isopropanol, Methylethyl Ketone, ….... [Loss on drying should be less than 0.5%]
· Class 1 residual solvents to be avoided, but are they always avoidable?
No. It is critical to avoid. General cases as follows :
1. Starting Material : e.g. Benzene in early steps in synthesis.
2. By-products from chemical reaction: e.g. Benzene as a Grignard-by-product.
3. Impurity in another residual solvents: e.g. Benzene as an impurity in toluene.
But it is need for control.
· What is Starting Material ?
A material used in the synthesis of a drug substance that is incorporated as an important element into the structure of the drug substance. Starting materials are usually available from commercial sources.
Intermediate is a material produced during API processing that undergoes further molecular change or purification before it becomes the API.
It may be isolated or may not be isolated (in suet).
· What is API (or) Drug Substance ?
Any substance or mixture of substances intended to be used in the manufacturing of a drug (medicinal) product and that, when used in the production of drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.
· What is Medicinal (or) Drug Product ?
The dosage form in the final immediate packaging intended for marketing.
· What is the general procedure for customer complaints handling ?
A complaint by Customer, Medical Professional and Regulatory Body is a formal expression of dissatisfaction with the quality of one of the company’s products.
Category – I Critical Defect:
A defect having a significant impact on product quality and / or safety and likely to have serious and / or harmful effect on the patient. (e.g. Product mix ups, label mix ups, adverse drug reaction).
Everyone concerned should at every stage expedite their action so as to reply to the complainant within 24 hours – 3 days from the receipt of complaint at the initiator, depending upon severity of the complaint.
Category – II Major Defect:
A defect, other than a critical defect, that is likely to result in a failure or reduction in the suitability of use of a unit for its intended purpose. (e.g. Reduction in potency, changes in disintegration time, dissolution, broken tablets).
Everyone concerned should at every stage expedite their action so as to reply to the complainant within 15 days from the receipt of complaint at the initiator
Category - III Minor Defect:
A defect that is not likely to reduce material feasibility of the unit of product for its intended purpose or as departure from established standards having little bearing on the effective use or operation of the unit. (e.g. Missing tablets / capsule, smudging of over printed matter, missing blisters, missing cartons, missing foils).
Everyone concerned should at every stage expedite their action so as to reply to the complainant within 30 days from the receipt of complaint at the initiator
· How many types of Deviations ?
Any planned or unplanned departure from an approved instruction or established standard is a deviation.
Planned Deviation :
A planned departure is a proposed change to any approved procedure, document or specification prior to execution. E.g. change in packing batch size of a batch as per customer’s requirement.
Unplanned Deviation :
An unplanned departure is an unexpected event that requires a change to any approved procedure, document or specification. It is usually discovered after the fact, E.g. A sudden change in the temperature / humidity in the manufacturing area, or temperature change during a drying cycle outside the specified range.
Major Deviation :
Deviation, which may have impact upon the identity, quality, purity, strength, stability, safety and efficacy or physical characteristic of the product.
Pre-approval is required before implementation for such types of deviations.
Minor Deviation :
Change, which may not have impact upon the identity, quality, purity, strength, stability, safety, efficacy or physical characteristic of the product.
Pre-approval is required before implementation for such types of deviations. In case of deviation is occurred same shall be reported to concerned department head and record in BPR and quality assurance with justification and supporting documents like CAPA, quality data of particular stage where deviation is occurred and final step where deviated batches are use.
· What is Skip analysis ?
Periodic or skip testing is the performance of specified tests at release on pre-selected batches and / or at predetermined intervals, rather than on a batch-to-batch basis with the understanding that those batches not being tested still must meet all acceptance criteria established for that product.
This represents a less than full schedule of testing and should therefore be justified and presented to and approved by the regulatory authority prior to implementation.
This concept may be applicable to, for example, residual solvents and microbiological testing, for solid oral dosage forms.
It is recognized that only limited data may be available at the time of submission of an application.
This concept should therefore generally be implemented post-approval. When tested, any failure to meet acceptance criteria established for the periodic test should be handled by proper notification of the appropriate regulatory authority(ies).
If these data demonstrate a need to restore routine testing, then batch by batch release testing should be reinstated.
· What is Internal Audit ?
In order to verify compliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule.
Audit findings (Non-conformances) and corrective actions should be documented and brought to the attention of responsible management of the firm.
Agreed corrective actions should be completed in a timely and effective manner.
General Types of Non-conformances:
Critical: Non-conformance, which may have direct impact on quality of product.
Major : Non-conformance, which may have indirect impact on quality of product.
Minor : Non-conformance, which may not have impact on quality of product.
· What is OVI ?
OVI : Organic Volatile Impurities are described in USP. This test is in effect until July 1, 2008.
There are many different solvents which are used in pharmaceutical manufacturing. USP mandates that at least six of these solvents be monitored in finished products : Benzene, Chloroform, 1,4-Dioxane, Ethylene Oxide, Methylene Chloride and Trichloroethylene.
Organic Volatile Impurities details are given in USP <467>.
· What is ICH ?
ICH is International Conference on Harmonization
.
Established in 1990 among the European Union, Japan, and United States.
Committed to reducing duplication during research and development of new drugs while safeguarding
Quality (chemical and pharmaceutical QA)
Safety (in vitro and in-vivo pre-clinical studies)
Efficacy (clinical studies in human subject)
Multidisciplinary (cross-cutting topics)
ICH has developed
over 40 guidance documents mostly addressing technical/regulatory requirements for registering new human drug products.
· What are ICH-Quality guidelines ?
Q1 è Stability
Q1A(R2): Stability Testing of New Drug Substances and Products
Q1B : Stability Testing : Photo stability Testing of New Drug Substances and Products
Q1C : Stability Testing for New Dosage Forms
Q1D : Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products
Q1E : Evaluation of Stability Data
Q1F : Stability Data Package for Registration Applications in Climatic Zones III and IV
Q2 è Analytical Validation
Q2(R1) : New title: Validation of Analytical Procedures: Text and Methodology
Previously: Text on Validation of Analytical Procedures
Validation of Analytical Procedures: Methodology (in Q2(R1))
Q3 è Impurities
Q3A(R2) : Impurities in New Drug Substances
Q3B(R2) : Impurities in New Drug Products
Q3C(R3) : Impurities: Guideline for Residual Solvents
Impurities: Guideline for Residual Solvents (Maintenance)
PDE for Tetrahydrofuran (in Q3C(R3))
PDE for N-Methylpyrrolidone (in Q3C(R3))
Q4 è Pharmacopoeias
Q4A : Pharmacopoeial Harmonisation
Q4B : Regulatory Acceptance of Analytical Procedures and/or Acceptance Criteria (RAAPAC)
Q5 è Quality of Biotechnological Products
Q5A(R1) : Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin
Q5B : Quality of Biotechnological Products : Analysis of the Expression Construct in Cells Used for Production of
r-DNA Derived Protein Products
Q5C : Quality of Biotechnological Products : Stability Testing of Biotechnological/Biological Products
Q5D : Derivation and Characterisation of Cell Substrates Used for Production of Biotechnological/Biological Products
Q5E : Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process
Q6 è Specifications
Q6A : Specifications : Test Procedures and Acceptance Criteria for New Drug Substances and New Drug
Products: Chemical Substances (including Decision Trees)
Q6B : Specifications : Test Procedures and Acceptance Criteria for Biotechnological/Biological Products
Q7 è Good Manufacturing Practice
Q7 : Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
Q8 è Pharmaceutical Development
Q9 è Quality Risk Management
Q10 è Pharmaceutical Quality System
· What is the need of system suitability test ?
This test is used to verify that the resolution and reproducibility of the system are adequate for the analysis to be performed.
System suitability tests are based on the concept that the equipment, electronics, analytical operations, and samples constitute an integral system that can be evaluated as a whole.
System suitability is the checking of a system to ensure system performance before or during the analysis of unknowns.
Parameters such as plate count, tailing factors, resolution and reproducibility (%RSD retention time and area for six repetitions) are determined and compared against the specifications set for the method.
These parameters are measured during the analysis of a system suitability "sample" that is a mixture of main components and expected by-products.
· How many cases of stability conditions are in place ?
As per ICH – Q1A, There are three cases are in place.
1. General Case :
Long term storage condition 25° + 2° C / 60% + 5% RH or 30° + 2° C / 65% + 5% RH
12 months (Initial, 3rd, 6th, 9th, 12th months) minimum time periods to be covered.
Intermediate storage condition 30° + 2° C / 65% + 5% RH
12 months (Initial, 6th, 9th, 12th months) minimum time periods to be covered.
Accelerated storage condition 40° + 2° C / 75% + 5% RH
6 months (Initial, 3th, 6th) minimum time periods to be covered.
It is up to the applicant to decide whether long term stability studies are performed at 25° + 2° C / 60% + 5% RH or 30° + 2° C / 65% + 5% RH.
If 30° + 2° C / 65% + 5% RH is the long-term condition, there is no intermediate condition.
If long term studies are conducted at 25° + 2° C / 60% + 5% RH and significant change occurs at any time during 6 months testing at accelerated condition, additional testing at the intermediate storage condition should be conducted.
2. Refrigerator Case :
Long term storage condition 5° + 3° C
12 months (Initial, 3rd, 6th, 9th, 12th months) minimum time periods to be covered.
Accelerated storage condition 25° + 2° C / 60% + 5% RH
6 months (Initial, 3th, 6th) minimum time periods to be covered.
Data from refrigerated storage should be assessed according to the evaluation section of this guideline, except where explicitly noted below.
If significant change occurs between 3 and 6 months testing at the accelerated storage condition, the proposed retest period should be based on the real time data available at the long term storage condition.
It is considered unnecessary to continue to test a drug substance through 6 months when a significant change has occurred within the first 3 months.
3.Freezer Case :
Long term storage condition - 20° + 5° C
12 months (Initial, 3rd, 6th, 9th, 12th months) minimum time periods to be covered.
· What is the general procedure to estimation of Retest Period or Shelf Life ?
Stability data evaluation for Retest Period or Shelf Life estimation for Drug Substances or Products (excluding Frozen Products)
| Data on all attributes at all storage conditions and evaluate each attribute separately | ||||||
|
| ||||||
| Significant change at accelerated condition within 6 months
| ||||||
| ¯ | ¯ | |||||
| No | Yes | |||||
| ¯
| ¯ | |||||
| Little or no change in long- term data
| Proposed to be stored in a refrigerator | |||||
| ¯ | ¯ | ¯ | ||||
| Yes | No | Yes | No | |||
| ¯
| ¯ | ¯ | ¯ | |||
| Little or no change in Accelerated data
|
Long-term data satisfying to statistical analysis | Change in Accelerated data with in 3 months |
Change in Intermediate data | |||
| ¯ | ¯ | ¯ | æ | å | ¯ | |
| Yes | Yes | No | Yes | No | ||
| ¯ | ¯ | ¯ | ¯
| ¯ | ||
| Statistical analysis is not required | If backed by relevant supporting data | If backed by relevant supporting data
| ●●●● | Long-term data satisfying to statistical analysis | ||
|
¯ |
¯ | |||||
| ¯ | ¯ | ¯ |
| Yes | No | |
|
|
|
|
| ¯ | ¯ | |
| ● | ● | ●● |
|
If backed by relevant supporting data
|
If backed by relevant supporting data | |
|
|
|
|
| ¯ | ¯
| |
|
|
|
|
| ●●● | ●●●● | |
● Y = Up to 2X but not exceeding X + 12 months è General Case
Y = Up to 1.5X but not exceeding X + 6 months è Refrigerator Case
●● Y = Up to 1.5X but not exceeding X + 6 months è General Case
Y = Up to X + 3 months è Refrigerator Case
●●● Y = Up to X + 3
●●●● Y = Up to 1.5X but not exceeding X + 6 months
●●●●● No extrapolation is required
Y = Proposed retest period of shelf life. X = Period covered by long-term dat.
What is Reprocessing ?
Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps that are part of the established manufacturing process.
Reprocessing of intermediates and APIs is generally acceptable.
If reprocessing is used for a majority of batches, it should be included as part of the standard manufacturing process.
Continuation of a process step after an in-process control test shows it is incomplete is considered part of the normal process, not reprocessing
What is Reworking ?
Subjecting an intermediate or API that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality material.
Reason for non-conformance should be investigated before reworking batches.
Reworked batches should be subjected to appropriate evaluation, testing, stability testing, if warranted, and documentation to show that the reworked batches are of equivalent quality to that produced by the original process.
Impurity profile of each reworked batch should be compared against batches manufactured by the established process.
Additional analytical methods may be needed if routine methods are inadequate to characterize reworked batches :
Concurrent validation is appropriate
Protocol should define
Rework procedure
How performed and expected results
Interim results if only one batch
What is Mother Liquor
· ?
The residual liquid that remains after crystallization or isolation processes that may contain :
Unreacted materials / Intermediates / Levels of the API and/or impurities
.
What about the Recovery of Materials/Solvents
?
Recovery of solvents, reactants, intermediates or the API from mother liquor or filtrate is acceptable.
Approved procedures should exist for recovery.
Recovered materials meet specifications and are suitable for their intended use.
Solvents can be recovered and reused in the same processes or different processes provided recovery procedures are controlled and monitored.
Ensure solvents meet appropriate standards before reuse or co-mingling.
Fresh and recovered solvents can be combined if adequate testing shows suitability for use in manufacturing.
Use should be adequately documented.
Generic Drug (Generics) is a drug which is produced and distributed without patent protection.
A generic must contain the same active ingredients as the original formulation.
In most cases, it is considered bioequivalent to the brand name counterpart with respect dose, strength, route of administration, safety, efficacy, and intended use.
In most cases, generic products are not available until the patent protections afforded to the original developer have expired.
When generic products become available, the market competition often leads to substantially lower prices for both the original brand name product and the generic forms.
The time it takes a generic drug to appear on the market varies.
Drug patents give twenty years of protection, but they are applied for before clinical trials begin, so the effective life of a drug patent tends to be between seven and twelve years.
· What is OTC ?
Over-the-counter (OTC) drugs are medicines that may be sold without a prescription, in contrast to prescription drugs.
The name "over-the-counter" is somewhat confusing to some, since these items can be found on the shelves of stores and bought like any other packaged product in some countries or in others may be bought "over the counter" from the pharmacy, while prescription drugs are sold at a pharmacy counter.
The term likely dates back to before self service shopping became common, when most goods were obtained by requesting them from a clerk at a sales counter; while prescription drugs required a visit to the doctor first, these drugs could be purchased "over the (sales) counter" just like other goods.
Some medicines considered safe in general terms might be available in general stores, supermarkets, gas stations etc.
The rules vary considerably from country to country.
· What are Herbal Medicine ?
Herbal medicine, also called botanical medicine or phytomedicine, refers to the use of any plant's seeds, berries, roots, leaves, bark, or flowers for medicinal purposes.
Long practiced outside of conventional medicine, herbalism is becoming more mainstream as up-to-date analysis and research show their value in the treatment and prevention of disease.
· What about Expiry and Retest ?
When an intermediate is intended to be transferred outside the control of the manufacturer’s material management system and an expiry or retest date is assigned, supporting stability information should be available (e.g. published data, test results).
An API expiry or retest date should be based on an evaluation of data derived from stability studies. Common practice is to use a retest date, not an expiration date.
Preliminary API expiry or retest dates can be based on pilot scale batches if
The pilot batches employ a method of manufacture and procedure that simulates the final process to be used on a commercial manufacturing scale; and
The quality of the API represents the material to be made on a commercial scale. A representative sample should be taken for the purpose of performing a retest.
· What about validation ? How many types of Validations are in place ?
Process Validation is the means of ensuring, and providing documentary evidence that processes (within their specified design parameters) are capable of repeatedly and reliably producing a finished product of the required quality.
Validation
should extend to those operations determined to be critical to the quality and purity of the API.
Critical parameters/attributes are normally identified during the development stage or from historical data, along with ranges necessary for reproducible operations.
Process Parameters
: Temperature/ Pressure/ Vacuum/ Time (Duration)/ Flow Rate/ Cooling Rate/ Agitation Speed.
1. Prospective Validation :
Normally performed for all API Processes
Validation of API process should be completed before commercial distribution of the final drug product manufactured from that API
2. Concurrent Validation :
Conducted when data from replicate production runs are unavailable:
Limited number of API batches produced
–API batches produced infrequently.
API batches produced by a validated process that has been modified.
Batches can be released and used in production of drug products for commercial distribution based on thorough monitoring and testing of the API batches.
3. Retrospective Validation
Exception for well established processes used without significant changes to API quality due to changes in:
Raw materials / Equipment / Systems / Facilities / Production Process
It may be used where :
Critical quality attributes and critical process parameters have been identified.
Appropriate in-process acceptance criteria and controls have been established
Process/Product failures attributed mostly to operator error or sporadic equipment failures unrelated to equipment suitability.
Impurity profiles have been established for existing API
Batches should be representative of all batches produced during the review period, including those that failed specifications
–Sufficient in number to demonstrate process consistency.
Retained samples can be tested
Periodic Review-Validated Systems
Systems/processes should be periodically evaluated to verify that they are still operating in a valid manner.
No need for revalidation if significant changes have not been made and a quality review confirms system or process consistently produces acceptable material.
· Which is Sterile API ?
A sterile API is an API that has been subjected to additional processing steps to remove microorganisms, particles and/or endotoxins.
· What is the general procedure for Out of Specifications handling ?
Any out-of-specification result obtained should be investigated and documented according to a procedure.
This procedure should require analysis of the data, assessment of whether a significant problem exists, allocation of the tasks for corrective actions, and conclusions. Any re-sampling and/or retesting after OOS results should be performed according to a documented procedure.
Out-of-specification (OOS) investigations are not normally needed for in-process tests that are performed for the purpose of monitoring and/or adjusting the process.
Out-Of-Specification batches should not be blended with other batches for the purpose of meeting specifications.
Each batch incorporated into the blend should have been manufactured using an established process and should have been individually tested and found to meet appropriate specifications prior to blending.
Field Alert Reports : For those products that are the subject of approved full and abbreviated new drug applications, regulations require submitting within 3 working days a field alert report (FAR) of information concerning any failure of a distributed batch to meet any of the specifications established in an application (21 CFR 314.81(b)(1)(ii)). OOS test results on these products are considered to be one kind of "information concerning any failure” described in this regulation. Unless the OOS result on the distributed batch is found to be invalid within 3 days, an initial FAR should be submitted. A follow-up FAR should be submitted when the OOS investigation is completed.
· How many types of Qualifications are in place ?
Before starting process validation activities, appropriate qualification of critical equipment and ancillary systems should be completed.
Qualification is usually carried out by conducting the following activities, individually or combined:
Design Qualification (DQ) : documented verification that the proposed design of the facilities, equipment, or systems is suitable for the intended purpose.
Installation Qualification (IQ) : documented verification that the equipment or systems, as installed or modified, comply with the approved design, the manufacturer’s recommendations and/or user requirements.
Operational Qualification (OQ) : documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges.
Performance Qualification (PQ) : documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications.
· What is NIOSH ?
NIOSH : The National Institute for Occupational Safety and Health.
The following information can be obtain from NIOSH :
Immediately Dangerous to Life and Health Concentrations (IDLHs)
International Chemical Safety Cards (WHO/IPCS/ILO)
NIOSH Manual of Analytical Methods (NMAM)
NIOSH Pocket Guide to Chemical Hazards (NPG)
OSHA Sampling & Analytical Methods
Recommendations for Chemical Protective Clothing
Specific Medical Tests Published for OSHA Regulated Substances
Toxicologic Review of Selected Chemicals
2000 Emergency Response Guidebook (U.S. Department of Transportation)
· What is the importance of Cleaning Validation ?
We know, there are three types of cleanings during API manufacturing :
Batch to batch cleaning
Periodic thorough Cleaning
Product to Product Cleaning
Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality. For example, in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed by subsequent purification steps.
Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability.
The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples to be obtained and how they are collected and labelled.
Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).
Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method’s attainable recovery level should be established. Residue limits should be practical, achievable, verifiable and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component.
Equipment cleaning/sanitization studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products).
Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these procedures are effective when used during routine production. Equipment cleanliness can be monitored by analytical testing and visual examination, where feasible. Visual inspection can allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling and/or analysis.
· Original DMF is only with fresh solvents. If we wish to use recovered solvents in the manufacturing process. What would be the filing category for such variation ?
The proposed variation will relax the specification of the solvents used in the process and therefore this will fail the Type IB criteria for minor changes to the manufacturing method for the active.
Hence, the active manufacturing method change, together with associated widening of solvent specifications, should be submitted as a single Type II Standard application.
If the original method of active manufacture is the subject of a DMF, then this application will require to be supported by replacement DMF pages in CTD format.
[It is the comment received from variation queries team of EU (MHRA, London)]
· What is Change Controls ?
A formal change control system should be established to evaluate all changes that may affect the production and control of the intermediate or API.
Written procedures should provide for the identification, documentation, appropriate review, and approval of changes in raw materials, specifications, analytical methods, facilities, support systems, equipment (including computer hardware), processing steps, labelling and packaging materials, and computer software.
Any proposals for GMP relevant changes should be drafted, reviewed, and approved by the appropriate organisational units, and reviewed and approved by the quality unit(s).
The potential impact of the proposed change on the quality of the intermediate or API should be evaluated.
A classification procedure may help in determining the level of testing, validation, and documentation needed to justify changes to a validated process.
Changes can be classified (e.g. as minor or major) depending on the nature and extent of the changes, and the effects these changes may impart on the process.
Scientific judgment should determine what additional testing and validation studies are appropriate to justify a change in a validated process.
When implementing approved changes, measures should be taken to ensure that all documents affected by the changes are revised.
After the change has been implemented, there should be an evaluation of the first batches produced or tested under the change.
The potential for critical changes to affect established retest or expiry dates should be evaluated. If necessary, samples of the intermediate or API produced by the modified process can be placed on an accelerated stability program and/or can be added to the stability monitoring program.
Current dosage form manufacturers should be notified of changes from established production and process control procedures that can impact the quality of the API.
· What is Degradation study ?
The purpose of this study is to determine the stability indicating nature of the methods used in analysis of stability studies. These are designed to increasing the rate of chemical (or) physical degradation of a drug substance by using exaggerated storage condition.
Degradation studies will carried out under the following conditions.
Acid Degradation Study [e.g. HCL]
Base Degradation Study [e.g. NaOH]
Peroxide Degradation study [Hydrogen Peroxide]
Thermal Degradation Study
Humidity Degradation Study
Photo Degradation Study
The analyte should show a minimum of 5 – 10% degradation by any one (or) more degradation methods.
The method should be able to detect the degradation. Peak purity of the analyte should meet the requirements. The method should not show any hidden impurity peaks at the retention time of the analyte.
What is expected with regard to OOT
· ?
Any out-of-trend result obtained should be investigated and documented according to a procedure.
This procedure should require analysis of the data, assessment of whether a significant problem exists, allocation of the tasks for corrective actions, and conclusions.
Any re-sampling and/or retesting after OOT results should be performed according to a documented procedure.
Typically that would be as part of our Annual Product Review.
Deviations even the non-critical deviation can be good indication of need to make some sort of mechanical change.
So that the operator can follow the instruction without deviating.
ICH-Q7 is not clear about trending of non-critical deviation, but it is a good business practice to do so.
· What about Potable Water, Purified Water and Water for Injection?
Potable Water
Meets National Drinking Water Regulations.
40 CFR Part 141.
Periodic monitoring in-house as well as periodic certificates from municipality (if applicable).
Potable water acceptable for preparation of USP drug substances.
Purified Water
Obtained by a suitable process, usually one of the following: Deionization / Reverse Osmosis / Combination
.
Purified water often used in later isolation and purification steps
.
Purified Water Systems monitoring :
Weekly monitoring of system for :
•Microbial quality
•TOC
•Conductivity
Water For Injection
Water purified by distillation or reverse osmosis.
Prepared from water complying with the U.S. EPA National Primary Drinking Water Regulations.
Contains no added substance.
WFI Systems monitoring :
Microbial quality and endotoxin :
•Daily system monitoring
•Each use point at least weekly
TOC and Conductivity :
•Weekly system monitoring
•Can be taken from worst case point (end of loop, return to tank)
Water used in the manufacture of APIs should be demonstrated to be suitable for its intended use.
Unless otherwise justified, water should at a minimum, meet WHO guidelines for drinking (potable) water.
If tighter chemical and/or microbiological specifications are necessary, these should be established.
Water used in final isolation and purification steps of a non-sterile API intended for producing a sterile drug product should be monitored and controlled for:
Total Microbial Counts /
Objectionable Organisms /
Endotoxins.
| Test | Potable water | Purified water | Water for injection |
| Total organic count | None | 500 ppb | 500 ppb |
| Conductivity | None | As per USP table | As per USP table |
| Microbial Purity | 500 CFU / ml | 100 CFU / ml | 10 CFU / 100 ml |
| Endotoxin | None | None | 0.25 EU / ml |
· What is the flow to get Purified Water (D.M.Water / R.O.Water) ?
General flow for preparation of Purified Water :
Potable (Sump) Water
¯
Chlorination
¯
De-Chlorination à by using Sodium Meta Bisulphate
¯
Cation Extraction
¯
Anion Extraction
¯
Mixed Bed [Both Cation and Anion]
¯
Purified water
Monitoring to be done on : pH : 5 – 7 and Conductivity : 2.1 µs
Purified Water Generation :
Cation è MgCl2 + R-H à MgR + HCl Anoin è HCl + R-OH à RCl + H2O.
Purified Water Re-generation :
MgR + HCl à MgCl2 + R-H RCl + NaOH à NaCl + R-OH
Here : R-H and R-OH are Resins and MgR and RCl are existed resins.
Whenever the hardness / conductivity of water increase, Regeneration to be start.
Purified Water Validation
Generally three Phases (Phase-I, Phase-2 and Phase-3) are involved.
In Phase-1 and Phase-2, Monitoring to be done on :
Total Microbial Count : Not More Than 100 cfu / ml
Alert Limit : Not More Than 60 cfu / ml
Action Limit : Not More Than 80 cfu / ml
cfu : Colonies for Unit
Based on In Phase-1 and Phase-2 monitoring, we can tight the limits of Alert and Action limits for our system and we can make the sanitization schedule.
What are Controlled Area and Critical Area
· ?
Controlled Area :
Preparation or manufacturing area where non-sterile product, in-process materials and product-contact equipment surfaces, containers and closures are exposed to the environment.
Control nonviable and viable contaminants to reduce product /process bioburden.
Class 100,000 or Class 10,000.
Capping areas are now considered controlled manufacturing areas:
–Should be supplied with HEPA filtered air,
–Should meet class 100,000 conditions during static conditions.
Critical Area :
Aseptic processing area where sterile products, components or in-process products are exposed to the environment and no further processing will occur.
Air quality must be Class 100 during processing.
Local Class 100 areas are often utilized during open processing steps during drug substance manufacture.
The area just preceding the sterile core should be one classification higher than the core.
Main Components
:
Airborne nonviable particulate monitoring
Airborne viable contaminant monitoring
Viable contaminant monitoring of surfaces
Viable contaminant monitoring of personnel
Temperature and humidity monitoring
Pressure differential monitoring
HEPA and High-Efficiency Filters :
HEPA is an acronym that stands for high-efficiency particulate air filter. It is used in the final stages of air cleaning, to remove very fine particles.
A HEPA filter, by definition, removes 99.97% of particles of 0.3 μm size.
HEPA filters are usually located downstream of heating and cooling coils in air-handling systems.
They are used in Class 100 work stations, in single or double filtration of air, to provide sufficient cleaning before the distribution of laminar air to the work space.
Attention should be paid to the seal between the filter element and its frame, which is a major source of leaks and failures in the system.
Federal Standard 209E:
Airborne Particulate Cleanliness Classes in Clean Rooms and Clean Zones
Approved by the GSA for use by all Federal Agencies
Frequently referenced for controlled environment particulate requirements: Classes 100, 10,000 and 100,000 (based on particles > 0.5µ)
HVAC Validation and Maintenance Considerations :
Air velocity, airflow patterns and turbulence should be validated; smoke studies to determine flow patterns during static and dynamic conditions
HEPA filter integrity and efficiency testing
Air pressure differentials
Temperature and Humidity :
Control of temperature and humidity required for aseptic processing areas
Generally 65°F and 35-50% humidity are average
Too high - Increases personnel shedding / Too low - Increase static electricity
Temperature should be controlled throughout all manufacturing areas
Temperature and humidity should be monitored and controlled in warehouse areas where temperature/humidity sensitive raw materials are stored
If not able to control humidity, need procedure to follow if humidity exceeds limit
Pressurisation :
Rooms should be made as air-tight as possible, so that the air-handling system can build pressure or reduce pressure in particular rooms.
Although air pressure differentials diminishes when doors are opened, the air must still continue to flow from the higher to the lower pressure space.
A pressure differential of 10 to 15 Pascals (Pa) should be set during design.
The pressure difference exerts a force on the door which can be calculated.
In order to obtain a pressure difference of 12 Pa, a velocity of approximately 2.8m/s must be maintained through all openings or leaks in the room.
If the openings are large, higher air velocities will be required.
A warning system should be provided to indicate failure in air supply.
Where differential pressures are required between adjacent areas, suitable monitoring equipment (i.e. manometers) must be installed.
The pressure differences should be recorded regularly or otherwise documented.
During the initial stages of design, each room must be assigned a cleanliness classification, according to its function. The classification adopted by PIC/S / ICH / ISO / etc. to GMP for medicinal products.
The guidance given for the maximum permitted number of particles in the “at rest” condition corresponds approximately to the US Federal Standard 209 E and the ISO classifications as follows:
| Classification | Nonviable ( > 0.5 µ) | Viable (CFU) | ||
| Ft3 | M3 | Ft3 | M3 | |
| Class 100 | 100 | 3,530 | 0.1 | 3.5 |
| Class 10,000 | 10,000 | 353,000 | 0.5 | 18 |
| Class 100,000 | 100,000 | 3,530,000 | 2.5 | 88 |
Grades A and B correspond with Class 100 / ISO 5
Grade C with Class 10 000 / ISO 7
Grade D with Class 100 000 / ISO 8
The requirement and limit for this area will depend on the nature of the operations carried out. .
- What are Compendial and non-Compendial analytical procedures ? What is analytical validation ?
Compendial is nothing but Pharmacopoeial and non-compendial is nothing but non-Pharmacopoeial. The analytical procedure refers to the way of performing the analysis. It should describe in detail the steps necessary to perform each analytical test. This may include, but is not limited to, the sample, the reference standard and the reagents preparations, use of the apparatus, generation of the calibration curve, use of the formulae for the calculation, etc.
Standard parameters for inclusion in a study of analytical validation:
Specificity / Selectivity
Accuracy
Precision
Linearity and Range
LOD / LOQ
Standard and Sample Solution Stability
Robustness (Optional)
Specificity / Selectivity : Specificity is the ability to assess unequivocally the analyte in the presence of components which may be expected to be present. Typically these might include impurities, degradants, matrix, etc.
Lack of specificity of an individual analytical procedure may be compensated by other supporting analytical procedure(s).
This definition has the following implications:
Identification: to ensure the identity of an analyte.
Purity Tests: to ensure that all the analytical procedures performed allow an accurate statement of the content of impurities of an analyte, i.e. related substances test, heavy metals, residual solvents content, etc.
Assay (content or potency): to provide an exact result which allows an accurate statement on the content or potency of the analyte in a sample.
Accuracy : The accuracy of an analytical procedure expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the value found. This is sometimes termed trueness.
Precision :
The precision of an analytical procedure expresses the closeness of agreement (degree of scatter) between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions. Precision may be considered at three levels: repeatability, intermediate precision and reproducibility.
Precision should be investigated using homogeneous, authentic samples. However, if it is not possible to obtain a homogeneous sample it may be investigated using artificially prepared samples or a sample solution.
The precision of an analytical procedure is usually expressed as the variance, standard deviation or coefficient of variation of a series of measurements.
Repeatability :Repeatability expresses the precision under the same operating conditions over a short interval of time. Repeatability is also termed intra-assay precision.
Intermediate Precision : Intermediate precision expresses within-laboratories variations: different days,
different analysts, different equipment, etc.
Reproducibility : Reproducibility expresses the precision between laboratories (collaborative studies,
usually applied to standardization of methodology).
Detection Limit (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, depending on whether the procedure is a non-instrumental or instrumental. Approaches other than those listed below may be acceptable.
Based on Visual Evaluation : Visual evaluation may be used for non-instrumental methods but may also be used with instrumental methods. 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.
Based on Signal-to-Noise : This approach can only be applied to analytical procedures which exhibit baseline noise. Determination of the signal-to-noise ratio is performed by comparing measured signals from samples with known low concentrations of analyte with those of blank samples and establishing the minimum concentration at which the analyte can be reliably detected. A signal-to-noise ratio between 3 or 2:1 is generally considered acceptable for estimating the detection limit.
Based on the Standard Deviation of the Response and the Slope : The detection limit (DL) may be expressed as : DL = 3.3 s / S
where s = the standard deviation of the response
S = the slope of the calibration curve
The slope S may be estimated from the calibration curve of the analyte. The estimate of s may be carried out in a variety of ways, for example:
Based on the Standard Deviation of the Blank : Measurement of the magnitude of analytical background response is performed by analyzing an appropriate number of blank samples and calculating the standard deviation of these responses.
Based on the Calibration Curve : A specific calibration curve should be studied using samples containing an analyte in the range of DL. The residual standard deviation of a regression line or the standard deviation of y-intercepts of regression lines may be used as the standard deviation.
Quantitation Limit (LOQ) : The quantitation 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 quantitation 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.
Several approaches for determining the quantitation limit are possible, depending on whether the procedure is a non-instrumental or instrumental. Approaches other than those listed below may be acceptable.
Based on Visual Evaluation : Visual evaluation may be used for non-instrumental methods but may also be used with instrumental methods. The quantitation limit is generally 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.
Based on Signal-to-Noise Approach : This approach can only be applied to analytical procedures that exhibit baseline noise. Determination of the signal-to-noise ratio is performed by comparing measured signals from samples with known low concentrations of analyte with those of blank samples and by establishing the minimum concentration at which the analyte can be reliably quantified. A typical signal-to-noise ratio is 10:1.
Based on the Standard Deviation of the Response and the Slope : The quantitation limit (QL) may be expressed as: QL = 10 s / S
Where s = the standard deviation of the response
S = the slope of the calibration curve
The slope S may be estimated from the calibration curve of the analyte. The estimate of s may be carried out in a variety of ways for example:
Based on Standard Deviation of the Blank : Measurement of the magnitude of analytical background response is performed by analyzing an appropriate number of blank samples and calculating the standard deviation of these responses.
Based on the Calibration Curve : A specific calibration curve should be studied using samples, containing an analyte in the range of QL. The residual standard deviation of a regression line or the standard deviation of y-intercepts of regression lines may be used as the standard deviation.
Linearity : The linearity of an analytical procedure is its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample.
Range : The range of an analytical procedure is the interval between the upper and lower concentration (amounts) of analyte in the sample (including these concentrations) for which it has been demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity.
Robustness : The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage.
Examples of typical variations are:
- stability of analytical solutions;
- extraction time.
In the case of liquid chromatography, examples of typical variations are:
- influence of variations of pH in a mobile phase;
- influence of variations in mobile phase composition;
- different columns (different lots and/or suppliers);
- temperature;
- flow rate.
In the case of gas-chromatography, examples of typical variations are:
- different columns (different lots and/or suppliers);
- temperature;
- flow rate.
Sample Solution Stability : This study determines the time period after sample preparation during which the compound of interest remains stable in the HPLC apparatus under the described analytical conditions. Data to support the sample solution stability under normal laboratory conditions for the duration of the test procedures, e.g., 24 hours should be generated and provides an indication of its reliability during normal usage.
Other points to consider include:
Capacity Factor (k') : The capacity factor is a measure of where the peak of interest is located with respect to the void volume, i.e., elution time of the non-retained components. The peak should be well resolved from other peaks and the void volume. Generally, the value of k' is >2.
Precision/Injection repeatability (RSD) Injection precision expressed as RSD (relative standard deviation) or coefficient of variation (C.V.) indicates the performance of the HPL chromatograph which includes the plumbing, column, and environmental conditions, at the time the samples are analysed. It should be noted that sample preparation and manufacturing variations are not considered. A C.V. of ≤ 1% for n ≥ 5 is desirable.
Relative retention ( α ) : Relative retention is a measure of the relative location of two peaks. This is not an essential parameter as long as the resolution (R s) is stated.
Resolution (Rs) : Rs is a measure of how well two peaks are separated. For reliable quantitation, well separated peaks are essential for quantitation. This is a very useful parameter if potential interference peak(s) may be of concern. The closest potential eluting peak to the analyte should be selected.
Rs of >2 between the peak of interest and the closest potential interfering peak (impurity, excipient, degradation product, internal standard, etc.) is desirable.
Tailing factor (T) : The tailing factor, a measure of peak symmetry, is unity for perfectly symmetrical peaks and its value increases as tailing becomes more pronounced. As peaks asymmetry increases, integration and hence precision becomes less reliable. T of ≤ 2 is desirable.
Theoretical plate number (N) :Theoretical plate number is a measure of column efficiency, i.e., how many peaks can be located per unit run-time of the chromatogram.
N is fairly constant for each peak on a chromatogram with a fixed set of operating conditions. H or HETP, the height equivalent of a theoretical plate, measures the column efficiency per unit length (L) of the column.
Parameters which can affect N or H include peak position, particle size in column, flow rate of mobile phase, column temperature, viscosity of mobile phase and molecular weight of the analyte.
The theoretical plate number depends on elution time but in general should be >2000.
Methods have been developed and validated in the following technologies:
Confirmation of identity by NMR, IR, MS
Assay of components by GC, HPLC, Wet Chemistry
Organic impurities by GC, Ion chromatography
Trace elements and ions by Ion Chromatography
Chiral Purity by NMR and Chromatographies
A wide range of physical property measurements on products and formulations can also be carried, for example, viscosity (for liquid products), porosity (for marcroporous materials), and XRD (for crystalline materials).
· Check the views of expects observations on various deviation :
Critical Observation :
Lack of validation of sterilization process
Falsification of analytical results
Cleaning programmes not followed, dirty equipment and premises
No air filtration system to eliminate airborne contaminants that are likely to be generated during manufacturing and product filling
Batches failing in initial sterility tests released for sale based on second test without any investigation
Major Observation :
Damage (holes, cracks, paint chips) to walls / ceilings in manufacturing area where product is exposed
Stored equipment not protected from contamination
Incomplete testing of Raw material
Control samples of Raw material not maintained
In sufficient lighting in production area
Preventive maintenance not performed as per schedule
Minor Observation :
Un-trapped floor drains
In-sufficient distance between walls and pallets to permit cleaning
Access to production not restricted to authorised personnel
Incomplete written sanitation programme, but premises in acceptable state of cleanliness
· Other Important Information
CDER : Center for Drug Evaluation and Research
CFR : Code of Federal Regulations
IND : Investigational New Drug Application
There are two IND categories : 1. Commercial 2. Research (non-Commercial)
NDA : New Drug Application
ANDA : Abbreviated New Drug Application (ANDA
EIR : Establishment Inspection Report
21 CFR Part 11 : Electronic Records and Electronic Signatures
21 CFR Part 210 : Current Good Manufacturing Practice In Manufacturing, Processing, Packing or Holding of Drugs.
21 CFR Part 211 : Current Good Manufacturing Practice For Finished Pharmaceuticals
NDS : New Drug Submission
ANDS : Abbreviated New Drug Submission
HPFB : Health Products and Food Branch
USP : United Stats Pharmacopoeia
Ph.Eur. / EP : European Pharmacopoeia
· Ranbaxy recalls 73 million pills from US market – Economic Times
In what is possibly the first product recall by an Indian pharma company in the US, Ranbaxy Laboratories is voluntarily pulling out 73 million tablets of 600 mg and 800 mg dosages of Gabapentin from the US retail market after discovering impurities outside the approved specification limit. The drug is used for treating pain in the nerves.
Gabapentin is manufactured at Ranbaxy’s USFDA-approved Simour unit in Himachal Pradesh. The company has been marketing the drug in the US since 2005. The market size of the drug for 600 mg and 800 mg dosages, which the company is recalling, was $964 million in 2005, according to IMS figures. According to a USFDA notification posted last week, India’s largest drug maker has already initiated the process of recalling the 73 million tablets of 600 mg and 800 mg in 100 and 500-tablet bottles.
A Ranbaxy Laboratories spokesperson said: “Ranbaxy Pharmaceuticals is carrying out a voluntary recall of all lots of its 600 mg and 800 mg Gabapentin tablets at the retail level as it found the presence of related substances permitted in the products to be outside the approved limit.”
· India, Canada to collaborate on pharma opportunities—Business Standard
The drug regulatory agencies of India and Canada are planning to collaborate on improving the quality of drugs traded between the two countries, besides helping the industry in both the countries to tap the opportunities in the field of generic medicines and drug development.
The Canadian regulator Health Canada and Drug Control General of India (DCGI) would meet this week to discuss the Mutual Recognition Agreement (MRA) for the transfer of clinical data pertaining to drug safety, inspection of manufacturing sites and other quality control issues, said Supriya Sharma, director general, Therapeutics Directorate, Health Canada.
The proposed collaboration is good news for Indian generic drug exporters since Canada is the world’s eighth-largest pharma market, accounting for prescription drug sales worth $18 billion a year.
· Names of Important Health Authorities
USA - Food and Drug Administration (FDA)
Europe - European Union Drug Regulatory Agency (Eudra)
EMEA - European Medicines Evaluation Agency
UK - Medicines and Healthcare Products Regulatory Agency (MHRA)
Germany - Homburg Authority for Social Affaires, Family, Health & Consumer Protection [BfArM]
http://heads.medagencies.org/germany.html
Portugal - Instituto Nacional da Farmácia e do Medicamento
http://www.infarmed.pt/index2.html
France - French Health Products Safety Agency
Spain - Agencia Española del Medicamento
Norway - Norway Medicines Board
http://www.legemiddelverket.no/
Sweden - Medical Products Agency
http://www.mpa.se/eng/index.shtml
Finland - National Agency for Medicines
http://www.nam.fi/english/index.html
Italy - Ministero della Salute
http://www.ministerosalute.it/medicinali/
Australia - Therapeutic Goods Administration (TGA)
Bulgaria - Bulgarian Drug Agency
http://www.bda.bg/web_engl/main.htm
Canada - Therapeutic Products Directorate (TPD)
http://www.hc-sc.gc.ca/hpb-dgps/therapeut/htmleng/index.html
Chile - Chile Regulatory Agency
Denmark - The Danish Medicines Agency
http://www.laegemiddelstyrelsen.dk/index_en.htm
Estonia - State Agency of Medicines
Hong Kong - Hong Kong Department of Health Welfare and Food
http://www.fwfb.gov.hk/eindex.html
India - Ministry of health and family welfare
Ireland - Irish Medicine Board
Japan - Ministry of Health, Labour and Welfare (MHLW)
http://www.mhlw.go.jp/english/
Russia - Ministry of Health of the Russian Federation
Switzerland - Swiss Medic
Anthology of Information :
ICH / PIC/S / EMEA / EDQM & Health Care / USFDA / HAS / TGA / MHRA / APIC / etc.
Note : Please consider that this transcript is only for updating and sharing the Knowledge.
If any inaccuracy is there in above preparation. Please update me to precise myself.
No comments:
Post a Comment