Saturday, April 23, 2016

Rapid Microbiology Methods in the Pharma

Rapid microbiology methods have long been essential tools of the clinical and food industry microbiology laboratories. Swift diagnosis of infectious diseases by clinical labs and the need for prompt test results from perishable food items have been strong incentives for the use of rapid methods. The pharmaceutical industry, however, has not been as quick to embrace rapid microbiology despite the potential advantages. Faster microbiology test results would provide better control over the manufacturing process. More rapid microbiology assays would also allow for earlier release of product. One of the explanations offered by the pharmaceutical industry for not using rapid microbiology methods is the uncertainty over regulatory acceptance. The process of evaluating, validating and implementing rapid microbiology test methods can be an expensive and time consuming task. Industry has been reluctant to expend precious resources when regulatory approval of the new method may be in doubt.
This article will provide an overview of microbiology testing in the pharmaceutical industry and will look at where rapid microbiological testing methods could fit into the manufacturing process. The issues involved with validation of rapid microbiology methods will be considered with regard to CDER review expectations. Finally, current FDA initiatives that could facilitate the use of rapid microbiology will be described.
Microbiological Test Methods
Microbiological tests for pharmaceuticals fall into several categories. One category involves release tests for drug products such as microbial limits testing of non-sterile drug products or sterility testing of parenterals and ophthalmics. Environmental monitoring tests include testing air, water, surfaces and personnel for viable microorganisms. Bulk drug product or components can also be tested for bioburden. Finally, some drug products are required to demonstrate antimicrobial effectiveness as part of the pharmaceutical development process. All these tests traditionally involve growth of microorganisms. Many of these tests involve compendial methods such as USP Chapters <51> (Antimicrobial Effectiveness Testing) [1], <61> (Microbial Limits Tests) [2] and <71> (Sterility Tests) [3]. The use of compendial test methods provides several advantages. Compendial test methods require minimal validation work on the part of the applicant before acceptance by regulatory authorities. The current compendial tests are also simple to execute and the results are easy to understand (colonies on a plate or turbidity in a liquid culture) even for a non-microbiologist. However, these growth-based tests have some drawbacks. They are slow, requiring several days to two weeks or more incubation. Growth of the microorganisms is limited by the medium and the incubation conditions used for the assay. Even though they have performed more or less adequately, the existing traditional microbiological methods are far from perfect.
There are many examples of rapid microbiology methods either in use, or in development, that could be of use for pharmaceutical manufacturing. The test methods can be grouped into the following three categories according to their uses: qualitative, quantitative and identification. Qualitative tests provide a yes/no answer to the question of microbial contamination. Asterility test is probably the most common qualitative test. Quantitative rapid methods provide a numerical value for the microbial contents of a sample and include conventional microbial limits tests. Quantitative test methods can also replace sterility tests, as long as they are sensitive enough to detect a single organism. Identification tests provide a name (or at least a description) of a microorganism. Various types of rapid identification tests have been available for many years, largely due to advances in clinical microbiology. However, test methods designed for clinical isolates are not always effective at identifying organisms found in a manufacturing environment. This is because the phenotypic databases used to support the clinical ID systems are drawn primarily from clinical isolates and may not contain adequate representation from other sources of microorganisms.
A rigorous scientific validation is a critical part of obtaining regulatory approval for a rapid microbiology method. There are two aspects of a new test method that should be addressed. Does the method work (in general), and is the method appropriate for the specific sample(s) to be tested? The general evaluation of a test method can be performed by the prospective user or literature references can be used to support the method. It is important to note that the user should not have to repeat the general method evaluation if the method is already in widespread use for a similar purpose. The suitability of the test method for the proposed samples should be established by using the samples with the method to determine inhibition or enhancement.
A new method should be at least equivalent (not inferior) to the existing method. Since the existing methods are predominantly the growth-based compendial methods, this comparison should not be a large hurdle for a new method. In order to determine equivalence between the old and new method, a number of criteria should be examined [4]. The essential elements for validation can vary somewhat depending on the type of test being studied (i.e., quantitative, qualitative or identification). The validation criteria are best examined experimentally using samples spiked with known organisms. Although parallel testing using the old and new methods has been suggested in determining equivalence, this is often not necessary or advisable. Parallel testing of samples that contain few microorganisms (or none) can be particularly problematic due to sample variation. Multiple samples taken from the same batch may give different results. The following sections will cover the various elements involved in validation of a rapid microbiology method.
Accuracy – A test for accuracy is a determination of the closeness of the results of a new test method with the expected results. Since the expected results are usually based on the existing method, a test of accuracy is essentially a comparison between the old and new methods. The results for a new quantitative method should not be significantly lower than the old method, although it is acceptable for the new method to give higher counts. Higher counts using the new method can be an indication of increased accuracy. Assessing the accuracy of an identification method can be more complex since the new and old method may give different results.
Specificity – A measure of the range of organisms a test method can detect. Using the term specificity can be somewhat misleading, since the wider the range the test has, the better the test. A new method should not have a narrower range than the existing method. The range of organisms used to test specificity should be representative of the types of organisms a test is likely to encounter. Using organisms isolated from the product/production facility would be very useful for assessing specificity. It should be recognized that an experimental protocol cannot be expected (nor is it necessary) to test every potential isolate.
It should be noted that some rapid microbiology methods can detect a significantly wider range of organisms than the traditional methods they would replace. This is particularly true for rapid methods that do not rely on microbial growth. This could potentially lead to results above the traditional alert and action levels. In order to allow for the difference between the new and old methods, the acceptance limit can be increased. The reason(s) for increasing the limit should be clearly explained and justified scientifically.
Precision – A measure of the repeatability/reproducibility of the test method. Anew method should be at least as precise as the old method. Precision is particularly important for identification methods since trending isolates can be difficult if the same organism is assigned different identities each time it is isolated.
Limit of Detection/Limit of Quantification – The lowest number of organisms that can be detected or counted. Limit of detection is particularly important for qualitative tests such as sterility. A sterility test should be able to detect a single viable organism. However, experimentally testing this capability is difficult due to problems associated with preparing a challenge sample that contains only one viable organism. Using samples with low numbers of organisms (e.g., 1-10 CFU) should be sufficient to assess limit of detection.
Range – The upper and lower limits of quantification. Range is an important characteristic for a potential user of a test method but is not necessarily important for determining equivalence. A test with limited range may require testing of multiple dilutions to be sure that the microorganisms in the sample are within the useful range of the method. Since the traditional method of enumeration (plate count) already has a fairly limited range (30-300 CFU/plate [2]), it should not be difficult for a rapid method to demonstrate equivalence to the existing method.
Linearity – The results of a quantitative method should be linear over the useful range of the method.
Ruggedness/Robustness – These characteristics reflect the ability of a test method to tolerate slight deviations in test parameters and still provide accurate results. The parameters varied often include reagents, operators and test equipment. Ruggedness and robustness are probably best assessed by the test vendor who will have ready access to multiple lots of reagents and multiple pieces of equipment.
FDA Initiatives
As was stated at the beginning of this article, one of the reasons cited by industry for not using rapid methods has been uncertainty over FDA acceptance. FDA has started several initiatives that should facilitate industry adoption of rapid microbiology methods. The first of these programs is the Process Analytical Technology initiative (PAT) [5]. Traditionally, pharmaceutical manufacturers use batch processes with end-product testing to confirm product quality and thus verify the suitability of the process. The PAT initiative was started specifically to encourage industry to use new innovative technologies to analyze and control the manufacturing process. One of the goals of PAT is continuous real-time quality assurance. Even though the current rapid microbiology methods may be primarily end-product tests, they can still offer increased control and understanding of the process by providing faster results. The PAT initiative will encourage use of rapid microbiology by providing specific regulatory handling for PAT submissions. Users of PAT are encouraged to meet with the agency to discuss their proposed uses of new technologies. Applications containing rapid microbiology will be reviewed by CDER reviewers trained in the technologies, and inspections will be carried out by FDA personnel who are trained in rapid microbiology. It is hoped that the PAT initiative will encourage industry to take advantage of rapid microbiology.
Another FDA program that should have an impact on rapid microbiology is the Pharmaceutical cGMPs for the 21st Century initiative. There are several aspects of this initiative that should prove helpful for introduction of rapid microbiology. First, there will be a dedicated and specially trained pharmaceutical inspectorate. These investigators will be provided advanced training specific to inspecting pharmaceutical manufacturing facilities. In addition to the pharmaceutical inspectorate, there will be product specialists available to go on inspections. These product specialists will include microbiologists with experience in rapid microbiology. These product specialists will provide further expertise as part of pharmaceutical inspections and ensure that rapid microbiology methods are evaluated in an appropriate scientific manner. Finally, a formal dispute resolution process will be set up to resolve disagreements that arise during pharmaceutical inspections [6]. The dispute resolution process could be helpful in settling differences of opinion involving introduction of rapid microbiology methods. The various aspects of the Pharmaceutical cGMPs for the 21st Century initiative should provide assurance to industry that their efforts to utilize rapid microbiology methods will be scientifically assessed.
Regulatory Submissions
The appropriate pathway for rapid microbiology submissions to FDA is best determined through direct dialogue with the agency. As mentioned above, the PAT initiative recommends discussion with FDA regarding all aspects of implementation for new process analytical methods. Until rapid microbiology methods become more widespread in the pharmaceutical industry, it may be simplest to implement new rapid methods on a post-approval basis. It may also be useful to employ a comparability protocol to implement rapid microbiology methods for multiple products and/or facilities [7]. A comparability protocol for an analytical method is a detailed plan that specifies the validation experiments and acceptance criteria. The approval of a detailed validation protocol should greatly reduce requests for additional information to support the subsequent changes. An approved comparability protocol can also designate a reduced reporting category for changes covered by the comparability protocol.
The use of rapid microbiology methods by the pharmaceutical industry should offer many advantages. Receiving microbiology test results sooner will provide for better control and understanding of the manufacturing process via faster feedback. Appropriate validation of rapid microbiology methods is necessary to ensure that the test is suitable for its intended purpose. However, it should be noted that the existing traditional microbiological test methods leave a lot of room for improvement. Therefore, it is not necessary to demonstrate that a new rapid method is flawless, only that it is not inferior to the current method, and will thereby provide equivalent assurance of microbial quality. Current FDA initiatives described in this article should help assure industry of the agency’s understanding of the potential importance of rapid microbiology methods. These initiatives should also convince industry that FDA will assess rapid methods scientifically and not place undue regulatory burdens on firms interested in using these methods. There are many exciting potential uses for rapid microbiology methods in the pharmaceutical manufacturing process, and industry should not feel that FDA will be a hindrance to the appropriate use of these methods.
1. Chapter <51>, Antimicrobial Effectiveness Testing, USP 26, USPC, Inc., Rockville, MD, p. 2002, (2003).
2. Chapter <61>, Microbial Limits Tests, USP 26, USPC, Inc., Rockville, MD, p. 2006 (2003).
3. Chapter <71>, Sterility Tests, USP 26, USPC, Inc., Rockville, MD, p. 2011 (2003)
4. Technical Report No. 33, Evaluation, Validation and Implementation of New Microbiological Testing Methods, PDA Journal of Pharmaceutical Science and Technology, Supplement TR33, vol. 54, no 3 (2000).
5. Draft Guidance for Industry, PAT – A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance, FDA (2003).
6. Draft Guidance for Industry, Formal Dispute Resolution: Scientific and Technical Issues Related to Pharmaceutical CGMP, FDA (2003).
7. Draft Guidance for Industry, Comparability Protocols – Chemistry, Manufacturing, and Controls Information, FDA (2003).  

why we use sodium salicylate for UV chamber calibration?

sodium salicylate is used as phosphor(light illuminating substance)to check the uv radiation and electrons so it is used an calibration for uv chamber 

Biggest Career Mistakes of Your Life & future

1.      Assuming that you know everything

2.      Forgetting to network

3.      Not being prepared for meetings

4.      Ignoring the value of business cards

5.      Engaging in office drama

6.      Arriving to meetings late

7.      Not asking for more work when you’re bored

8.      Being satisfied doing the minimum amount of work necessary

9.      Not sharing your career goals with your leader

10.  Not reading up on your industry

11.  Forgetting to make a LinkedIn page

12.  Over-sharing personal stories at work

13.  Burning bridges when leaving a job

14.  Dressing unprofessionally

15.  Not proof-reading your e-mails

16.  Believing that you’re going to be a VP right out of college

17.  Not seeing the value in entry-level positions

18.  Not learning from your mistakes and failures

19.  Failing to seek out a mentor

20.  Thinking that once you choose a job field, you’re stuck with it forever

21.  Not having an updated resume available at all times

22.  Failing to join associations and groups pertaining to your industry

23.  Being a negative person

24.  Not taking initiative and turning down all new projects

25.  Forgetting to thank people who help you

26.  Not asking for help when you need it

27.  Failing to admit that you’re overwhelmed with your workload

28.  Trying to convince yourself that you love your job when you don’t

29.  Overestimating your abilities and not being honest about them

30.  Turning down training courses

31.  Not keeping track of all your accomplishments

32.  Making career decisions for anyone other than yourself

33.  Not actively looking for a job when you’re not happy with the one you have

34.  Thinking that it’s too late in life to change careers

35.  Making premature judgements of others

36.  Over-promising results, and then failing to deliver

37.  Not having a system for managing e-mails

38.  Failing to understand when and how you’re most productive

39.  Assuming that everyone around you thinks the same way you do

40.  Failing to accept diversity as an asset to your team

41.  Not caring how your actions affect other people

42.  Having an emotional IQ of zero

43.  Being scared to ask questions

44.  Making decisions that impact others without consulting with them first

45.  Believing that you need to be an a-hole to be taken seriously

46.  Taking jobs just for the money

47.  Not sharing your knowledge with others

48.  Letting your ego guide your decisions

49.  Not thinking big-picture

50.  Complaining about problems instead of offering solutions

51.  Failing to embrace change

52.  Being intimidated by new technology

53.  Not pushing yourself outside of your comfort zone

54.  Not giving yourself time to re-charge

55.  Not standing up for what you’re worth

Friday, April 15, 2016


AADA: Abbreviated antibiotic drug application
ADE: Adverse drug event
ADME: Absorption, distribution, metabolism, and excretion
AHU: Air Handling Unit
ANDA: Abbreviated new drug application
ANVISA: Agência Nacional de Vigilância Sanitária (National Health Surveillance Agency Brazil)
AP: Applicants Part (of EDMF)
API: Active pharmaceutical ingredient
APR: Annual product review (APQR – Annual product quality
AQL: Acceptable quality level
AR: Analytical Reagent
ASHRAE: American Society of heating, Refrgeration and
Air Conditioning Engineers
ASM: Active Substance Manufacturer
ASMF: Active Substance Master File
AST: Accelerated stability testing
ASTM: American Society for Testing and Materials
BA/BE: Bioavailability/bioequivalence
BCS: Biopharmaceutical classification system
BET: Bacterial Endotoxin Test
BFS: Blow Fill Seal
BI: Biological Indicator
BMR: Batch Manufacturing/Processing Record
BOD: Biological Oxygen Demand
BOM: Bill of Materials
BOPP: Biaxially Oriented Polypropylene
BP: British Pharmacopoeia
BPR: Batch Packaging Record
BRMS: Biologics Regulatory Management System
BSE: Bovine spongiform encephalopathy (mad cow disease)
CAPA: Corrective and preventive action
CBE: Changes being effected
CBER: Center for Biologics Evaluation and Research (FDA)
CCIT: Container closure integrity test
CDER: Center for Drug Evaluation and Research (FDA)
CDSCO: Central drug standard control organization (India)
CEP: Certification of suitability of European Pharmacopoeia monographs
CFR: Code of Federal Regulations
CFU: Colony Forming Unit
cGMP: Current Good Manufacturing Practices
CIP: Clean in place
CMC: Chemistry, manufacturing and controls
CMS: Continuous monitoring system
COA: Certificate of analysis
COS: Certificate of suitability
COPP: Certificate of Pharmaceutical Products
CPP: Critical Process Parameter
CQA: Critical Quality Attribute
CTD: Common technical document
DMF: Drug master file
DOP: Dioctyl Phthalate
DQ: Design Qualification
EDMF: European drug master file
EDQM: European Directorate for the Quality of Medicines
EH&S: Environmental health and safety
EIR: establishment inspection report (FDA)
EMEA: European Medicines Agency (formerly European Medicines Evaluation Agency)
EP: European Pharmacopoeia
EPS: Expanded polystyrene
ETP: Effluent Treatment Plant
EU: Endotoxin unit
EU: European Union
FAT: Factory Acceptance Testing
FBD: Fluid-bed dryer
FDA: Food and Drug Administration,United States
FDC: Fixed Dose Combination
FEFO: First expiry first out
FG: Finished Goods
FIFO: First in first out
FMEA: Failure modes and effect analysis
FOI: Freedom of information
GAMP: Good automated manufacturing practice
GC: Gas Chromatography
GCLP: Good clinical laboratory practice
GCP: Good clinical practice
GDP: Good distribution practice
GEP: Good engineering practice
GGP: good guidance practice
GIT: Gastrointestinal Tract
GLP: Good laboratory practice
GMO: Genetically modified organism
GMP: Good manufacturing practice
GPT: Growth Promotion Test
GRAS/E: Generally recognized as safe and effective
GRP: Good review practice
HACCP: Hazard analysis critical control point
HDPE: High Density Polyethylene
HEPA: High efficiency particulate air (filter)
HPLC: High performance liquid chromatography
HSA: Health Sciences Authority, Singapore
HVAC: Heating, ventilating, and air conditioning
ICAH: International Conference on Harmonisation
IH: In house
IM: Intramuscular
IND: Investigational new drug
INDA: Investigational new drug application
IP: Indian Pharmacopeia
IPA: Isopropyl Alcohol
IPS: In process control
IQ: Installation qualification
IR: Immediate release
ISO: International Organization for Standardization
ISPE: International Society for Pharmaceutical Engineering
IV: Intravenous
JP: Japanese Pharmacopoeia
KOS: Knowledge organization system
LAF: Laminar air flow
LAL: Limulus Amoebocyte Lysate
LD: Lethal dose
LD50: Lethal dose where 50% of the animal population die
LDPE: Low Density Polyethylene
LIMS: Laboratory Information Management System
LIR: Laboratory Investigation Report
LOD: Loss on drying
LOD: Limit of detection
LOQ: Limit of quantification
LR: Laboratory Reagent
LVPs: Large Volume Parenterals
MA: Marketing Authorisation
MAA: Marketing Authorisation Application
MAC: Maximum Allowable Carryover
MCC: Medicines control council (South Africa)
MDD: Maximum daily dose
MFR: Master Formula Record
MEDSAFE: Medicines and medicinal devices safety authority (New zealand)
MHRA: Medicines and Healthcare products Regulatory Agency (UK)
MOA: Method Of Analysis
MSDS: Material Safety Data Sheets
NCE: New chemical entity
NDA: New Drug Application
NF: National Formulary
NIR: Near Infra Red Spectroscopy
NON: Notice of non-compliance (Canada)
ODI: Orally Disintegrating Tablet
OQ: Operation Qualification
OSD: Oral Solid Dosage
OSHA: Occupational Safety And Health Administration
OTC: Over-the-counter
OOS: Out of specification
OOT: Out of trend
PAC: Post-approval changes
PAO: Poly alpha olefin
PAT: Process Analytical technology
PET: Preservative efficacy test
PET: Polyethylene
PIC/S: Pharmaceutical Inspection Co-operation Scheme
PLC: Programmable Logic Control
PQ: Performance Qualification
PVC: Polyvinyl Chloride
PVDC: Polyvinylidene Chloride
PW: Purified Water
QA : Quality Assurance
QC: Quality Control
QbD: Quality by design
QM: Quality Manual
QSD: Quality System Dossier
QSM : Quality System Management
QMS: Quality Management System
RH: Relative humidity
RLAF: Reverse laminar air flow
RLD: Reference listed drug
RM: Raw material
RO: Reverse Osmosis
ROPP: Roll On Pilfer Proof
RS: Related Substance
SAL: Sterility Assurance Level
SAT: Site Acceptance Testing
SDN: Screening Deficiency Notice (Canada)
SIP: Sterilization in place/Steam in place
SLS: Sodium Lauryl Sulphate
SMF: Site master file
SOP: Standard operating procedure
SPE: Society for Pharmaceutical Engineering
SUPAC: Scale-up and post approval changes
SVP: Small Volume Parenteral
TC: Thermocouple
TDS: Total Dissolved Solids
TGA: Therapeutics goods administration (Australia)
TOC: Total organic carbon
TSE: Transmissible spongiform encephalopathy
USFDA: United states foods and drugs administration
USP: United States Pharmacopeia
USP-NF: United States Pharmacopeia-National Formulary
URS: User Requirement Specification
VAI: Voluntary action indicated
VMP: Validation Master Plan
WFI: Water for injection
WHO: World Health Organisation
WL: Warning letter ,

Monday, April 11, 2016

why use toline in resolution in uv calibration?

The Spectral Bandwidth (SBW) of a spectrophotometer is the
basis of establishing its ability to resolve absorbtion
lines seperated by small differences in wavelength. If a
substance that you need to measure has an absorbtion line at
257.4nm and there is an interfering line at 260.0 nm you
need to establish whether your spectrophotometer can resolve
the two lines seperately or "mixes" the two absorbtion lines
into a single line which would give erroneous results.

Toluene in Hexane is used as a reference for the calculation
of SBW. The ratio of the absorbtion of the solution when
read at a maxima (around 268.7nm) and at a minima (around
267.0nm) relates directly to the SBW of the instrument being
assessed. Regular use of this technique will assure that the
resolution of your instrument is within the required range
for your work 

Thursday, April 7, 2016

Cleanroom Guideline Revised Version-ISO 14644-1:2015-12

Cleanroom Guideline Revised Version-ISO 14644-1:2015-12

New version  includes the following changes:

1. The number of measuring points is no longer calculated as the square root of the surface but given in a table.

2. 5 µm particles for ISO 5 has been dropped from the limit value table.

3. No more statistical UCL calculation: there is no need to perform an observation of all measuring points in the room any longer.Each single measuring point is considered individually and has to meet the limit value.

4. The tubing length to the particle counter should be less than 1 m.

5. The classification number, the sample volumes/ measuring period as well as the cancellation criterion remain unchanged compared to the version of 1999.


EU GMP Revised Annex 16 on QP Certification and Batch Release Effective from 15 April 2016

The European Commission has published the final version of the revised EU-GMP Guideline Annex 16 "Certification by a Qualified Person and Batch Release". Deadline for coming into operation is 15 April 2016.

As one important topic, it has been pointed out that the major task of a Qualified Person (QP) is the certification of a batch for its release. In this context, the QP must personally ensure the responsibilities listed in chapter 1.6 are fulfilled.  In chapter 1.7 a lot of additional responsibilities are listed which need to be secured by the QP. The work can be delegated and the QP can rely on the respective Quality Management Systems. However "the QP should have on-going assurance that this reliance is well founded" (1.7). Amongst these twenty-one tasks are for example:

Starting materials comply and the supply chain is secured, including GMP assessments by third parties

The necessary audits have been performed and the audit reports are available

Manufacturing and testing performance are compliant with the MA

Manufacturing and testing processes are validated

Changes have been evaluated and investigations completed

It is important to mention in this context that "the ultimate responsibility for the performance of an authorised medicinal product over its lifetime; its safety, quality and efficacy lies with the marketing authorisation holder (MAH). However "the QP is responsible for ensuring that each individual batch has been manufactured and checked in compliance with laws in force (…), in accordance with the requirements of the marketing authorisation (MA) and with Good Manufacturing Practice (GMP)" (see General Principles).

In the case that the QP has to rely on the correct functioning of the quality management system of other sites, the QP "should ensure that a written final assessment and approval of third party audit reports has been made". The QP should also "be aware of the outcome of an audit with critical impact on the product quality before certifying the relevant batches."

Another important section clarifies the role of the QP when it comes to deviations, implementing main features of the EMA Position Paper on QP Discretion (which was issued in February 2006 and updated January 2008). Chapter 3 of the draft describes the "handling of unexpected deviations". A batch with an unexpected deviation from details contained within the Marketing Authorisation and/or GMP may be certified if a risk assessment is performed, evaluating a "potential impact of the deviation on quality, safety or efficacy of the batch(es) concerned and conclusion that the impact is negligible." Depending on the outcome of the investigation and the root cause, the submission of a variation to the MA for the continued manufacture of the product might be required.

During the consultation phase, stakeholders expressed their concerns regarding the sampling of imported products. Now the new annex is clear on this: "Samples may either be taken after arrival in the EU, or be taken at the manufacturing site in the third country in accordance with a technically justified approach which is documented within the company's quality system. (…) Any samples taken outside the EU should be shipped under equivalent transport conditions as the batch that they represent."

The new annex is rather short on other importation requirements. These requirements will probably be defined in the new Annex 21.

Wednesday, April 6, 2016

How to do documentation in aseptic area?

Autoclavable Munising Paper

Image result for autoclavable paper a4We all know ,that in documentation  is very important in  pharma industry  we use A4 size paper for documentation

"Paper should is main source of contamination in sterile area-
so how can we do documentation without contaminating our clean rooms "

Autoclavable munising paper is widely accepted for documentation in aseptic area


The polymer impregnated substrate surrounds and bonds each individual cellulose fibre resulting in a cleanroom paper. The cellulose fibre core provides true paper characteristics giving problem free writing, printing and photocopying. Munising LP is auotoclavable, and benefits from extremely low static build-up and particulate generation.

  • Munising LP is Latex Free
  • The paper has a high degree of chemical resistance. The maximum loss of strength was 21% after soaking in the following 5% v/v H2SO4 2% w/w NaOH, Acetone, Ethanol and water. Tensile test on air-dried sheets.
  • Munising LP can be sterilised by gamma irradiation, ETO or steam without seriously impairing the sheet. The particle count remains at the normal, low level.
  • Microbe Testing - The yielded four colony forming units (CFU) according to micro pore filtration methodology and zero CFU according to Rodac plate methodology.
  • The paper has a flammability rating of "moderately flammable" Classification 2, according to the National Fire Protection agency (NFPA-702)
  • Using tests similar to those methods described in Federal Substances Act, CFR 16, Section 1500.41, it was determined that Munising LP would not be classified as primary skin irritant.
  • Tests from NAMSA state that the paper is non-cytotoxic (MEM elution with l929 mice fibre blast cells).

Tuesday, April 5, 2016

Why Sampling Plan is SQRT n+1 or √n+1 for Pharmaceuticals?

  • The sampling formula SQRT n+1 in pharmaceuticals and its recommendations in various guidelines.
  • Quality of pharmaceutical products majorly depends upon the sampling of the excipients and the active pharmaceutical ingredients. Proper sampling can give us confidence in our analysis. In other words we can say – sampling is a starting process but is has its importance.
  • Number of containers to be sampled is an interesting part of the raw material sampling because it we receive 5000 containers of an excipent then it shall be very difficult to sample all containers and it is difficult too to analyze the thousands of samples. In such cases sampling plans are used to reduce the sampling and analysis of large number of containers. Generally in pharmaceuticals,  SQRT (n+1) or √n+1 formula is used to determine the number of containers to be sampled. Where n is the number of containers received. This formula is used to reduce the sampling of the large number of containers of the excipents. Some companies have their own limitations as if containers are 10 or less, all containers shall be sampled.
  • WHO suggests 3 formulae of sampling for pharmaceutical ingredients in Technical Report Series TRS-929 - Annex 4, “WHO Guidelines for sampling of pharmaceutical products and related materials”.
  •  n-plan: This plan is used when the material is uniform and supplier is recognized and reliable. Sample can be taken from any part of the container. Samples are taken by using the formula n=1+√N. Sampling units are selected randomly and all containers shall be sampled if those are four or less in number.
  • p-plan: Samples are taken using this plan only when material is received from the reliable sources and identification of material is being done. Sampling is done by using the formula p=0.4√N and samples are collected in separate sample containers.
  • r-plan: r-plan is used when the material is suspicious and received from the unknown source. Sampling is done using the formula r=1.5√N. It gives the more number of samples than the n-plan to build the confidence level.
  • All samples are collected separately and transferred to quality control laboratory for identification. If sample passes the identification test; sample is analyzed for the assay.
  • Department of Human Health Services, Food and Drug Administration (FDA) clearly writes in 21 CFR Part 111 Docket No. 2007N–0186 that there are a lot of sampling plans but we use SQRT n+1 and also suggests to sample 4 from 10 containers, 11 from 100 containers and 32 from 1000 containers.
  • Therapeutic Goods Administration, Australia (TGA) states in its guideline “Sampling and testing of complementary medicines” that formula √n+1 can be used for the sampling of the excipents and sampling of the active material can be reduced.
Therefore, √n+1 is a widely accepted formula for the determination of the containers to sampled in pharmaceuticals and all major regulatory agencies recommend the same.

Sunday, April 3, 2016

Important things for autoclave

1. Testing of Steam for Porous Product Sterilization
Before commencing temperature testing the correct conditions must be satisfied. The first condition for sterilization of porous product is saturated steam quality. The ideal for steam sterilization is dry saturated steam and entrained water (dryness fraction ≥ 97%). The largest heat transfer occurs when the steam is at boundary conditions. If the steam is dry or contains gas then it cannot condense and its effectiveness is reduced.

Image result for autoclave2. Equipment Used for Testing

The equipment used must support 21 CFR Part 11 and must be of adequate accuracy. Testing with equipment that is not appropriate can be a major problem so also buy from a trusted vendor. As a small temperature range is required for accuracy (A few degrees) the accuracy of the equipment is very important for the overall measuring chain.

3. System Description of Autoclave

The first impression is very important when the qualification of critical equipment such as an autoclave is at stake. A good description of the system in a protocol shows that you understand how the process works and which critical points you need to keep under control. This description must contain the programs that are used, how they work, how many, where the control probes are located and what regulates this process.

4. Operating Instructions, Calibration and Maintenance

Before the temperature is tested it must be checked whether the operating instruction are valid, whether the instruments are calibrated and what was changed in the system since the last qualification occurred.
Operating Instructions must include parameters of sterilization, the scheme item and position of the control probes in the chamber. The emphasis is on the calibration of instruments because small errors in temperature can affect the Fo value to a great extent.

5. Procedure

One of the most common mistakes is inaccurate testing procedures. The test procedure must be unambiguous and accurate and must not leave the possibility for different interpretations.
Ambiguous: Put the thermocouple in a glass bottle.
Unambiguous: Put the thermocouple in a glass bottle at the contact between the bottom of the bottle and the side of the bottle (This is the most critical place to collect condensate).

6. Load

The most common objections are about loads. That they are not sufficiently described and that regular production does not reflect the qualified load being used.
This can be avoided by item photographing and releasing the same patterns in the protocol and work instructions. This will avoid the arbitrary interpretation of descriptive configuration.
Although sometimes this may seem trite the differences in the temperature profiles of the solution and air filters can be great. Pay special attention to the worst case loads and explain the rationale (mostly filter and silicone hose).

7. The Position of the Thermocouples

The position of the thermocouples must be unambiguous and precise to avoid different interpretations by individuals that perform tests or inspections. You do not want to enter into a debate about where the thermocouple is positioned.
Of course, the critical areas must be covered, and this must be explained in the rationale. When sterilizing liquid loads studies must be done to define coldest and warmest point for min and max load.

8. Acceptance Criteria in the Heat Penetration Tests

Since there are differences in the standards (e.g. PDA Technical Report and EN 285) it would be best if all eligibility criteria are taken into account. Special emphasis should be on equilibration time and temperature because it is a requirement for a good Fo.

9. Deviations

Deviations cannot be forgotten as they may be encountered regularly throughout the qualification process. A robust deviation management process should exist as they may impact the quality of the product. Good handling of deviations help us to improve our qualification, though they are often viewed negatively and not as a mechanism for process improvement.

10. Reports

The report should be accurate as it eliminates the use of data from the protocol and the ability to find errors in them. The report should contain the time and the date of tests, parameters, results related to temperature, BI results , positions of thermocouples, Fo and comparison of results from initial and previous qualification in order to see in which direction the process is moving.

Saturday, April 2, 2016

what is a difference between drug purity and drug potency?

Purity means other than impurity or absence of impurity & 
we are calculating by area normalization.

while Potency is content of that substances in the sample 
and calculating it on dried basis ie. LOD, water content , 
residual solvent.