Pharmaceutical Production - Science topic

1st time i watch a true Principal always saying correct words against worst media.I also reading regulary uttarbanga sambad and i like Jyoti Sarkar news very much because he is the true reporter always saying truth and gives vital news.But Pradyut Das type reporter is the black spot of media.

Generic medicine name means selling the product in name given by inventor to API like paracetamol, aspirin and so on.

But majority of pharma companies sell by branding the basic drugs either single salt or combinations. The major issue is how to carry drug to human body and ensure it is not dissolved in stomach. More over a now famous pharma compnay buys near expiry bulk drugs and repacks in own brand gives extended expiry date and offers at low prices. Most drugs are difficult to administer like to children, infants and old aged person. slow release medicines are thus invented where mini globes carrying drugs are produced and then put in a capsule. Suspensions are made for children. Many drugs are administered as nasal sprays. Hence purity index of chemical, method of administering it, its slow absorption and combination drugs where branding comes in. But major pharma makers exploits branding and give unfair inducements to drug stores and doctors and charge several times the cost. WE should also not forget huge research and development charges

To combat this governments made it compulsory to write generic brands and health system buys in bulk contracts

Fanny Diaz,

Yes, We can give you training for dissolution method development for QC as well as IVIVC.

You can send WhatsApp to following number.

Regards,

Tushar Gaikar

+91 9137675350/9920525272 or can message to me on +91 9833618555

A cost-effective option for a quick confirmatory test is the use of immunoassays such as EIA and ELISA, without investing in expensive specialized kits. Still, this may depend on the serotype you're working with.

The microbiolgical quality in the pharmocopia kept a modern apothecary " natural body care"

lockdown may help in reducing the air pollution in certain cities as the vehicular movement stopped. But in larger spectrum lockdown can not be a solution for the betterment of ecosystem.

You probably have hydrolysis of the ester bond. Ethanol evaporates and thus the concentration decrease of your API. Check the pH of the formulation and lower it with a buffer.

Dear Maryell,

The acute toxicity tests, most tests are conducted to determine the nature of any toxicity that can be produced by repeatedly dosing animals over an extended period. NOAEL and LC50 and LD50 are quite popular method. The highest exposure of a chemical, determined in toxicity tests etc., having no adverse effect (e.g., onset of sickness) even when the chemical is taken (exposed) daily for the rest of one’s life. In practice, mice, rats or other animals are forced to take a chemical for a certain period of time. This test is repeated several times at varying dose levels. The highest dose level causing no adverse effect in these tests is adopted as NOAEL (No Observed Adverse Effect Level).other related terms you could use in your study like; LOAEL (Lowest Observed Adverse Effect Level) NOEC (No Observed Effect Concentration) and LOEC (Lowest Observed Effect Concentration)

Use this formula for your concern. (NOAEL (No Observed Adverse Effect Level) value calculation.

Toxicity studies etc., / UFs (Product of Uncertainty Factors) [ to convert it to human NOAEL (Unit converts in e.g., mg/kg/day)].

TDI (Tolerable Daily Intake)=

NOAEL (No Observed Adverse Effect Level)

UFs (product of Uncertainty Factors)

ADI (Acceptable Daily Intake) and RfD (Reference Dose) are also used as terms having the same meaning as TDI.Graph you ca take between frequency of hazards vs chemical exposure.

The LD50 is defined as the lethal dose at which 50% of the population if killed in a given period of time; an LC50 is the lethal concentration required to kill 50% of the population.

Reference: https://www.nite.go.jp/en/chem/shiryo/ra/about_ra4.html

Ashish

Dear P J,

Each product or a set of pharma- products have a basis of usage of water and creation of ww, sw and others.

You need to evaluate on annual turn over basis the generation of wastes and produces produced.

Annual audit can be a good method, which would include all resources used for plant maintainance done in the year also.

Preferably, to get the actual feel of resources used, wasted or if any re-used, a site -visit and survey with questionaire is suggested.

Well wishes

Prof Ajit Seshadri.

Is there any guidelines for in process hold time study of semi-solid dosage form

Please take a look at this useful link.

You may refer

Counterfeit pharmaceutical product is a biggest challenge especially where pharma regulation is weak.

In my opinion, the greatest impact on the sale of pharmaceuticals has advertising in various media, promotion of pharmaceuticals in advertising campaigns conducted in various media, including new online media, besides public relations in the issue of shaping the image of the manufacturer, ie a specific pharmaceutical company, its strategy, mission and development , market share, information on production technology on pharmaceutical packaging, information on testing pharmaceuticals, on which country they are produced, according to which standards, in which normative realities shaping technical and security standards, impact on consumer health.

Best wishes

As you have mentioned that you found some out of control data, it clearly indicates that your problem is to set the control limits for the process. This is called phase-I or the base period. In the base period , when the process shows points beyond control limits, it is required to find whether they are due to assignable causes or not. It requires to remove those points from the analysis. Then one goes into phase-II where the chart will be used to monitor the process.

Also, do not get confused with specification limits and control limits. Because I found some practioners are confused between USL and LSL with UCL and LCL. Please refer to Statistical quality conrol book by DCMontgomery for better understanding.

Michal Svoboda

Thank you for your answer.

This is actually hold time study for bulk solution i.e. during production in the mixing tank, instead of stability studies of the finished product in final primary packaging. Therefore I'm only considering the product factor. I believe some products will be at higher microbial contamination risk than others, but I'm not sure whether strength will have an effect or not.

You can simply assay for increase in spoilage microbial load, depletion of vital elemental composition via microbial degradations and biiaccumulation, sensory evaluation without taste option...

You can assay for feed from different manufacturers using different preservatives.

A good preservative should maintain feed composition throughout the self life

Hazardous pharmaceutical product manufacturing

Shelf Life - the time period from when the product was manufactured to it’s ‘expiry date’ -i.e. The time period the product is expected to be safe , effective and fit-for-purpose provided it has been packaged and stored in recommended conditions throughout this period,

Expiry Date - all drugs tend to deteriorate /degrade from the point of manufacture and the ‘expiry date’ of a product is the end point of its shelf life taking into account a tolerance of degredation ( normally less than 10%). Degredation is normally due to hydrolysis (chemical degredation by water) or oxidation ( reaction with oxygen) or by microbiological contamination . Drugs produced in liquid forms ( e.g. Oral mixtures , injections) are generally less stable and degrade more quickly than the same drug in a solid formulation ( tablet /capsule) . Degredation is also temperature dependant , and some formulations are designed to be stored at room temp (25 degrees C) whereas some must be refrigerated ( 4–8 degrees C).

Half-life. This is usually a reference to the time taken for the body to eliminate 50% of the dose of drug after the time of administration. It varies with different drugs and between individual patients but ‘average’ half-lives’of drugs may be found in the literature. E.g. Most penicilllins - half lives around 20 mins , digoxin ( a heart medication) - half life = 36 hours - both assume normal kidney function etc.

To my best knowledge such detailed, batch related information is not available neither in th USA nor in the EU / EEA and is neither published by th FDA or EMA.

BUT critical and/or major GMP devations detected by FDA or competent EU GMP inspectorates during GMP inspections (EMA herself does not perform GMP inspections, these are conducted by the competent national authorities of the Member States) which lead to assessments of GMP non-compliance are reported i documents accessible by the public. The name of such reports published by USFDA are called Warning Letters accessible by the following link https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/default.htm

EU reports about GMP / GDP non-compliances detected during GMP inspections are published EudraGMDP data base http://eudragmdp.ema.europa.eu/inspections/logonGeneralPublic.do

You will find in both data bases a huge number of reports also including world famous companies like Bayer Leverkusen, etc.

Nephron Clin Pract. 2009;113(3):c125-31. doi: 10.1159/000232592. Epub 2009 Aug 12.

Tamimi NA1, Ellis P.

Author information

Drug development is an expensive, long and high-risk business taking 10-15 years and is associated with a high attrition rate. It is driven by medical need, disease prevalence and the likelihood of success. Drug candidate selection is an iterative process between chemistry and biology, refining the molecular properties until a compound suitable for advancing to man is found. Typically, about one in a thousand synthesised compounds is ever selected for progression to the clinic. Prior to administration to humans, the pharmacology and biochemistry of the drug is established using an extensive range of in vitro and in vivo test procedures. It is also a regulatory requirement that the drug is administered to animals to assess its safety. Later-stage animal testing is also required to assess carcinogenicity and effects on the reproductive system. Clinical phases of drug development include phase I in healthy volunteers to assess primarily pharmacokinetics, safety and toleration, phase II in a cohort of patients with the target disease to establish efficacy and dose-response relationship and large-scale phase III studies to confirm safety and efficacy. Experience tells us that approximately only 1 in 10 drugs that start the clinical phase will make it to the market. Each drug must demonstrate safety and efficacy in the intended patient population and its benefits must outweigh its risks before it will be approved by the regulatory agencies. Strict regulatory standards govern the conduct of pre-clinical and clinical trials as well as the manufacturing of pharmaceutical products. The assessment of the new medicinal product's safety continues beyond the initial drug approval through post-marketing monitoring of adverse events.

PMID: 19729922 DOI: 10.1159/000232592[Indexed for MEDLINE] Free full text

A re-est period should be derived from the stability information, and a retest date should be displayed on the container label if appropriate. See ICH Q1A(R2): Stability testing of new drug substances and products and ICH Q6A/B: Specifications.

Check the animal models for the indication:

Animal Models for Depression. Molecular Perspectives (Curr. Top. Behav. Neurosci. 2011, 7, 121-147).

Also see: Neurosci. Bull. 2010, Aug; 26(4), 327-37.

sodium valproate (molecular weight 166 g/mol) is the sodium salt of the weak acid valproic acid (molecular weight 144 mg/mol). Sodium is not the pharmacological active part, the valproate ion is the active part. 58 mg of valproic acid is equivalent to 58/144 = 0.402 mol valproate ion. This is equivalent to 0.402x166 = 67 mg. Thus the equivalent total amount is 133.2 + 67 mg = 200 mg of sodium valproate.

SAL @ 1/1000 is commonly used in Pharm industries but @121 oC for 16mins a probability of 1/100000000 can be obtained.

Enter your answer

There are too many variables in the question to be able to answer it.  Permitted levels of phthalates for human exposure seem to vary from country to country and often only apply to specific items (like the limits for toys, plastic containers and things like medical tubing and bags for using with a drip line).  If you look up the MSDS for each compound there will be some information there but that is not necessarily helpful when you are looking at a pharmaceutical product.  You would need to hunt around for information (if there is any) on the limits allowed for phthalates in a specific type of pharmaceutical - if this exists it will give different levels for an external cream to something you ingest.  In the USA there is increasing concern about the cumulative effects of phthalates as they are so ubiquitous in the environment and I don't think there is any agreement on how to assess a 'safe' level for this or how you would enforce it.  You also have a problem in that you don't know what proportion of your phthalates will leach, evaporate etc. and how much of that will get into the user of the product.  That would require testing and it would be hard to design a suitable experiment because of the issues mentioned above and the different levels of exposure people experience in their daily lives.  The only truly safe level of phthalates in pharmaceuticals is zero, or as near to that as you can get.

lm sorry I dont know about this subject

Dear Jehad,

Lactic acid may be used in injectable formulations for the production of biodegradable polymers and microspheres, such as poly(D-lactic acid), used in drug delivery systems.

for more on this compound, please see page 355 in the attached file.

Hoping this will be helpful,

Rafik

Dear Mohammed, 

From a regulatory standpoint and according to the ICH guidelines and understanding followed by EMA and WHO the applicant needs to submit at least 12 mo real-time stability data (plus the accelerated one) at the time of filing for a MA. From a scientific perspective I would say that, based only on the ICH Q1 stability accelerated conditions (40C/75%RH), it is not possible either as you will not generate enough data to estimate stability/degradation relevant kinetic parameters.

Answering to your question, I don´t know any guideline that allows the finished pharmaceutical product shelf-life to be estimated based only on stability accelerated conditions.

Regards, Luis

The degradation products and impurities assay(s) aren't typically used to estimate the pharmaceutical product shelflife...just the API.  But the degradation and impurities are important in the risk assessment of safety of the API and are assessed over the shelf life of the product.  Most jurisdictions have set some threshold limits for degradants/impurities on the basis that very low levels are unlikely to be harmful.  If your degradants/impurities are well characterised and have known toxicity profiles then an argument can be made to what allowable limits should be (provided the API remains within the prescribed assay limits)..likewise a degradant/impurity could render the pharmaceutical unsaleable if it reaches a toxic level prior to the API falling outside specified limits.

Dear Gaurav,

Generally, the term drying refers to the moisture separation solids, gases or liquids. For drying gases and liquids, adsorption is often used. The drying of solid products is particularly applicable to the food industry. During the heat drying of solids, moisture is removed from the product by evaporation. The drying process depends on the manner in which moisture is present in the product. Initially, there is first evaporation of the liquid to the surface of the product to be dried. Once this liquid has been removed, the drying affects the moisture present in the capillaries and pores. Since the forces capillaries and resistance to diffusion must be overcome, the drying rate decreases. For the crystal structures, the bound water may be removed by a strong warming and low drying rates.

In the field of engineering thermal processes, evaporation is the separation of the solvent solution. For example salt water contains a salt (solid dissolved) and a solvent (water). The addition of heat causes the evaporation and evacuation of the pure solvent present in the solution (in this example water). The concentration of dissolved solids (salt) in the residual solution is thus higher than before the heat input.

With my best regards

Prof. Bachir ACHOUR

Dear Hocine,

I know the following links which can help you.

Regards,

Abhishek

U can look at the abitec corporation and gattefosse company website.they also provide free gift samples

In my view, 'sustainable' refers to a process that can be carried out indefinitely, that is, there is an unlimited supply of raw materials and energy to supply the process. So the phrase 'ethically sustainable' is interesting because ethics doesn't usually deal with such quantities. It refers more to the social judgements that guide the behaviour of individuals and societies. So, are you asking whether societies are simply prepared to allow the present system of pharmaceutical patenting to continue? I  would imagine that the system has been created by governments on the advice of the pharmaceutical companies, so I would be very surprised if they were to turn round and suddenly admit that their systems were unethical and needed changing.

But governments are in a bind, too, because it can cost the best part of a $1billion to  research, develop, test, refine, retest and finally qualify some drug for human use. Who's going to pay for this unless the company has an effective patent? Should the taxpayer simply underwrite ALL pharmaceutical developments past a certain stage in return for a much more limited patent system? It's not an easy issue!

I presume this is the same way that petroleum-based light oils protect reactive metals like sodium and lithium... water doesn't pass through the oil, so water doesn't "ever" encounter the hygroscopic compounds whose stability would be compromised upon contact with water. 

Nearly every year I have students who forecast sales of pharmaceutical products. But you mention new products. That implies that you have very short series. This is a more serious aspect than measuring forecast accuracy. You don't say at what level you work (production, distribution, retail), and if the products will face competition or are new in their field. This will have a huge impact on the methods to use. Good luck.

± ethyl methyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate

From a RA standpoint the requested (to authorities) shelf-life must be based on real-time stability data and no extrapolation is allowed. According to WHO guidelines if accelerated stability was OK you could ask for extrapolation up to twice the real-time stability data (minimum of 12 mo real-time stability) but no more than 12 months extrapolation. Refer to Ali's attachments for details.

The impurities in Pharmaceuticals are regulated by Food and Drug Administration (FDA) and International Conference on Harmonization (ICH) guidelines. Because many solvents pose a major risk to human health, national and international regulatory bodies such as the United States Food and Drug Administration (U.S. FDA), the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), and the International Conference on Harmonization (ICH) require analysis for residual solvents in pharmaceutical drug substances, excipients and final products. In herbals,residual solvents may results from their use as an extraction solvent in liquid extracts and tinctures or when added as a diluents to liquid pharmaceutical preparation.

dear d. Karanam Thank you first of all.

This article was one of the references that  I followed in my project. and I applied the exact method that used, but unfortunately I did not get the same results..I am really Surprising why...