cGMP & QC

If you need access to the United States pharmacopoeia (USP) then you can get it by logging in through the IT Tallaght Library website. You can find the USP on the page at the link below. Just search for pharmacopoeia at the link below and click it. You will then be required to login using your IT Tallaght student details.

http://bit.ly/usptallaght

 

RefME is a platform I have talked about before as a useful piece of kit for managing your referencing. RefME has been purchased by another reference manager which has both free and premium (pay to use) versions called Cite this for me. RefME will shut down in due course so it might be worth considering moving to another manager. Cite this for me is a very simple to use reference manager but there are quite a few programs out there which offer both free and premium versions. A list of my top reference managers can be found below:

Zotero has chrome plugins to assist reference capture.

January 2017 Exam Timetables are now available here:

http://www.it-tallaght.ie/examtimetables

Ray D’arcy had Prof. Michael Barry of the NCPE (National Centre for Pharmacoeconomics) on his radio show. Prof. Barry discussed the recent orkambi decision and the role the NCPE has in the national formulary. Really interesting conversation and well worth a listen. The podcast can be downloaded from the link below:

NCPE on Ray D’arcy

One of your colleagues found a very good book on Pharma Science on the web and it’s available free. The title of the book is: Pharmaceutics: The Science of Dosage Form Design 2nd Edition By Micheal E. Aulton and can be found at the link below.

http://bit.ly/pharmascienceebook

As an update to a previous post on this please note there is a newer and more often updated free desktop publishing software known as Libreoffice. Not everyone has or can afford Microsoft Office but there are plenty of free packages out there that do much the same as Microsoft office and are similarly easy to use. You can get a free office suite of programs from many companies and organisations but one of my favourites is Libre Office. Select the version open office for your system here:

https://www.libreoffice.org/download/libreoffice-fresh/

Medicines manufactured by the pharma sector cost significant amounts of money to go from discovery to market. This can mean that many medicines when they launch are beyond the ability of most people to afford them. In most cases the largest purchaser of pharmaceuticals are countries. Countries buy the drugs for their own national formularies. In an ideal world everyone would get the drugs they need to treat their illnesses. This unfortunately is not the case. Countries have limited budgets with which to buy essential medicines. Pharmacoeconomics is the study of the value of one drug or drug therapy over another. In Ireland the NCPE (National Centre for Pharmacoeconomic Evaluation) takes on the task of deciding which drugs should be made available freely from the state. Their mission is:

…to facilitate healthcare decisions on the reimbursement of technologies, by applying clinical and scientific evidence in a systematic framework, in order to maximise population wellness. The NCPE assess evidence for comparative effectiveness and cost-effectiveness of technologies for use by patients in Ireland. This is done through assessment of evidence submitted by manufacturers and independent systematic review. The NCPE also undertake research to inform national guidelines for health technology assessment.

NCPE

The EMA (European Medicines Agency) which is the EU regulator of the pharmaceutical, bio-pharmaceutical and medical device sector currently has its head offices for all of Europe in London. Following the vote on Brexit, and once the UK follows through on leaving the EU, the EMA will have to fine a new home for it’s HQ in a European country. Ireland may be well placed to become home to the new HQ due to the size of the sector in the country. We’ll have to watch and wait for now.

In 2013 it was agreed by European Pharmaceutical Associations that a new policy around disclosure of payments was to be implemented by member Associations. The IPHA (Irish Pharmaceutical and Healthcare Association) who are a member of the EFPIA set up a website to document all payments made from Pharmaceutical companies in Ireland to Irish healthcare professionals. The code is voluntary unlike the open payments system in the US which came in under the sunshine act. The first data disclosed related to 2015 and was published in a central industry report on the IPHA website on 30th June 2016. As the code is voluntary, Irish healthcare professionals can refuse to be listed and currently according to the IPHA about 55% of them are partaking in the voluntary code. You can find more details at the links below:

Transfer of Value

An explanation of the code

Search the database

 

 

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If anyone would like to use an app instead of their browser when doing my in class revision quizzes feel free to download the app for Android or iPhone/iPad below.

Android:

https://play.google.com/store/apps/details?id=com.socrative.student

iOS

https://itunes.apple.com/us/app/socrative-student/id477618130

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The latest version of the Eudralex Volume 4, Good manufacturing practice (GMP) Guidelines can be found at this link:

http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm

It’s well worth having a look at to see how GMP documents, such as the site master file, can be laid out.

Clinical trial details that the US FDA is monitoring can be found at http://clinicaltrials.gov but if you want to see what’s happening in Europe check out http://clinicaltrialsregister.eu The European only launched recently (January 2016).

EU Clinical Trials Register

 

There’s a Moodle mobile app available for iOS and Android devices. It might be useful accessing information away from your PC/Mac. The apps are available from the links below:

iOS

Android

 

From the BBC website

Reckitt Benckiser, the maker of a range of Nurofen products based on the active ingredient ibuprofen lysine, has been ordered by an Australian court to remove a number of its products, including Nurofen Back Pain, Nurofen Period Pain, Nurofen Migraine Pain and Nurofen Tension Headache, from shop shelves.

The action was taken by the Australian consumer watchdog, Australian Competition and Consumer Commission (ACCC), who argued in court that there was no difference between the different branded drugs used to treat different types of pain but which all contained the same levels of the active ingredient, ibuprofen lysin. The Federal Court of Australia has given the company 3 months to remove the products from Australian shelves.

The move has no effect in other jurisdictions around the world but may prompt further investigations. A spokesperson for Reckitt Benckiser said “Nurofen did not set out to mislead consumers”.

Update: The UK’s Advertising Standards Authority (ASA) is now investigating a number of complaints made against Nurofen about an ad on Nurofen Express. Similar complaints are being investgated in New Zealand too.

If you’re looking for past papers for any subject you are studying you can get them from the ITT Dublin Library website at this link:

http://millennium.it-tallaght.ie/search/r

 

 

This is a short video on the basic operation of a spectrophotometer.

Once a patent expires for a drug (after 20 years) other manufacturers will step in to start selling the same drug but marketed as a generic. A recent investigation by skynews reported that the differences between some of these generic drugs (specifically pain killers) and their branded equivalents were few and far between.

…consumers in the UK are spending more on painkillers than ever before, a Sky News investigation reveals branded pills that claim to target pain can cost up to four times more than unbranded tablets…Jayne Lawrence, professor of biophysical pharmaceutics at Kings College London, said: “Some people believe that by taking a more expensive preparation, perhaps a branded formulation, they’ll get better pain relief.

“If it’s the same dose of drug, in the same formulation, the customer will experience no difference.”

Courtesy Skynews

Botulinum toxin is a neurotoxic protein (destructive to nerve tissue) produced by the bacterium Clostridium botulinumIt also has medical applications, when use in tiny quantities, including in the treatment of dystonia (a muscle contraction disorder) and muscle spasms in cerebral palsy. Probably it’s most famous application is as a cosmeceutical which prevents the development of wrinkles by paralysing facial muscles. The brand name for this product is Botox and is produced by Allergan in Ireland.

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There’s a very good explanation for what the function of the CDER (Center for drug evaluation and research) at the FDA’s own FAQ page found here:

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/FAQsaboutCDER/#1

Wikipedia also has a good definition:

CDER reviews New Drug Applications to ensure that the drugs are safe and effective. Its primary objective is to ensure that all prescription and over-the-counter (OTC) medications are safe and effective when used as directed.

I found a nice article explaining some of the key terms we’ve discussed in relation to sampling plans. Might be worth a read:

http://wps.prenhall.com/wps/media/objects/7117/7288732/65767_28_SuppG.pdf

 

Lot Tolerance Percent Defective (LTPD): The upper limit on the percentage of defects that a consumer is willing to accept.

Consumers Risk: The probability that a lot containing defects exceeding the LTPD will be accepted.

Producers Risk: The probability that a lot containing the AQL will be rejected.

Operating characteristics curve (OC): The ability of a sampling plan to discriminate between lots of high and low quality is described by it’s operating characteristics curve. The steeper the slope of the OC curve the more discriminating the sampling plan. It can be made steeper by increasing the number of samples to be tested or reducing the number of rejects acceptable.

This is a peer reviewed journal article on “Analytical techniques in pharmaceutical analysis” outlining the different techniques used in industry. The citation (Reference) is Siddiqui MR, AlOthman ZA, Rahman N. Analytical techniques in pharmaceutical analysis: A review. Arabian Journal of Chemistry. April 2013. The paper can be found here:

http://dx.doi.org/10.1016/j.arabjc.2013.04.016

The FDA publishes Guidance for Industry documents. One such document is for the Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production which details guidance that applies to chemistry-based laboratory testing of drugs regulated by CDER. It is directed toward traditional drug testing and release methods.

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The image below shows how Process Capability (standard deviation) relates to Process quality.

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Check out the video here for more information and it’s related video here

This video explains standard deviation and mean as well as cp/cpk

Pharmacopoeias are books which contain information on how to identify medicinal compounds. Some of the more common pharmacopoeias published include the European, United States and the WHO.

This is an example of a protocol for testing sterility from the WHO’s pharmacopoeia

TEST FOR STERILITY

Here is an example of the protocol for identifying the medicinal product Asprin (Acetylsalicylic acid).

Asprin-Acetylsalicylic acid Specification

Statistics is the study of the collection, organization, analysis, interpretation and presentation of data (wikipedia). To this end some averages (the middle) and standard deviations (the variation from the middle) are some of the basic calculations in statistics which we use every day. The average of three numbers can be calculated by adding them all together and dividing by the number of numbers there are. For example in the following sequence: 1, 2, 3 there are three numbers (we write this as “n=3”). The average can be calculated by adding them together: 1+2+3 = 6 and dividing this total by the number of numbers to calculate the average: 6/3=2. The average of 1, 2, 3 is 2. The “average” can also be called the “mean”. Both words describe the same thing. Symbol wise we can also call the “average” or “mean” x-bar and write it as an “x” with a line over as in: xbarSo the Average = Ave = Mean = xbar

The standard deviation is the difference between the x̄ and the other numbers in the sequence. we usually calculate standard deviation using calculators or excel but it can be easy to work out for some sequences. So back to the sequence 1, 2, 3 where the x̄ was 2 the standard deviation is 1 because x̄ + 1 is 3 (the upper number in our sequence) and x̄ – 1 is 1 the lower number in our sequence. Symbol wise we can also write the “standard deviation” as a p on it’s side: σ

So the Standard Deviation = StDev = σ

When we display data in figures to assess it’s quality we will often use histograms. These figures consist of an “x” and “y” axis. The x being the horizontal axis and the y being the vertical axis. Each axis is used to display data of some sort such as sample weight on the “x” axis and the number of samples of a particular weight on the “y” axis (also known as the frequency). If we re order the collected data on sample weights such that samples with the smallest weights are to the left of the “x” axis and the samples with the highest weights are to the right of the “x” axis we can in most cases produce a a bell shaped histogram such as the one below.

hist_normal

This is known as a “bell shaped curve” or “normal distribution” or a “Gaussian curve”.

According to the FDA 21 CFR 58.3 the definition of raw data is:

any laboratory worksheets, records, memoranda, notes, or exact copies thereof, that are the result of original observations and activities of a nonclinical laboratory study and are necessary for the reconstruction and evaluation of the report of that study. In the event that exact transcripts of raw data have been prepared (e.g., tapes which have been transcribed verbatim, dated, and verified accurate by signature), the exact copy or exact transcript may be substituted for the original source as raw data. Raw data may include photographs, microfilm or microfiche copies, computer printouts, magnetic media, including dictated observations, and recorded data from automated instruments.

The link below is to the FDA’s guide to electronic signatures and records – scope and application

 

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http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm125125.pdf

The United Nations Development Programme published a report on methods, tools and good practices for fighting corruption. The full report can be found by clicking Anticorruption-Methods-and-Tools-in-Health-final.

The report found 10 lessons were critical for fighting corruption:

Lesson one. There is no ‘one size fits all’ approach to mitigating corruption in the health sector. Practitioners need to give careful attention as to what potential strategy or strategies would work most effectively in view of the specific risks identified by use of diagnostics.
Lesson two. More than one anti-corruption intervention should be employed to deal with one risk. For example, wage increases may help to curb the likelihood of absenteeism, but they are likely to be more effective when there are systems in place to document absentee rates and when sanctions for absence are imposed.
Lesson three. Prioritization is key: governments and others involved in health projects and programming should prioritize areas of the health system that are most susceptible to corruption and implement appropriate interventions. Often even ‘low hanging fruit’ can produce significant anti-corruption impacts. For example, the act of posting medical supply and pharmaceutical product pricing can help deter price gouging. The identification of priority areas is particularly important when resources are scare.
Lesson four. It is important to work with other sectors. Corruption cannot be curbed in the health sector without the involvement of other critical sectors, such as infrastructure and finance.
Lesson five. Health policy goals should include anti-corruption considerations. Investments in health may be wasted unless anti-corruption strategies are built into all health projects. Preventative interventions can protect investments made.
Lesson six. Prevention is the best strategy: therefore, it is best not to wait for corruption to happen before beginning to deal with it. One of the biggest failings in the health sector is the implementation of anti-corruption interventions only after corruption is suspected or confirmed. Regular monitoring of the health sector for discrepancies in standards is vital.
Lesson seven. Numerous empirical diagnostic tools should be employed. Given the complexity of the health sector, more than one diagnostic tool may be of value to ensure accurate information. This also requires proper measuring and re-measuring. Regular ‘check-ups’ can measure how effectively anti-corruption strategies are working in a given point in the health care system.
Lesson eight. Partners with experience in implementing anti-corruption strategies and tactics should be identified and contacted for technical support. This study has identified a number of NGOs, international development institutions, research groups and experts involved in implementing anti- corruption strategies and tactics in the health sector.
Lesson nine. Broad participation in health policy and planning helps. Involving NGOs, citizens and designated experts in health budgeting, monitoring, and consulting, as a few examples, can help heighten transparency and lessen the likelihood of corruption.
Lesson ten. Good behaviour should be rewarded, and bad behaviour punished. This can be done by setting up appropriate incentive structures that help promote adherence to good behaviour, such as performance-based financing. It is also important to sanction those individuals who are engaged in corrupt activities where possible. This sends an important message that corruption is not tolerated.

Apart from outright corruption there are many important reasons for regulation of the pharmaceutical sector. The links below are to a few stories that indicate the need for regulation.

Pharmaceutical companies make huge profits and as a sector it is matched only by the banking sector for the largest profits. Many of the worlds best known pharma companies spend more on marketing then they do on R&D: http://www.bbc.com/news/business-28212223

The US Justice Department is so concerned about the marketing prowess of the pharma companies that it released a 2001 recording of a sales executive meeting for GSK which you can view here and the first 30 seconds speaks for itself.

When the US government brought in the affordable care act they also launched a website that patients/public could search to see what perks their doctor has received. It can be found here: https://openpaymentsdata.cms.gov/ A report into the site found some suprising statistics: http://projects.propublica.org/docdollars/ The types of work doctors do for pharma compneis include partaking in clinical trials, giving speeches and directly workign for a company.

Here is a list of what the fees to doctors are paid for: http://projects.propublica.org/docdollars/companies

Forbes magazine produced an article on the coffee supply chain with a very useful graphic indicating the many links that connect together to get you your daily coffee. You can see that at any point along this chain there is the possibility for corruption without regulation.

Vega-Typical-Supply-Chain-sRGB-1

The links below will take you to some of the common reasons for receiving FDA warning letters:

FDA warning letters: the most common violations highlighted

Analysis of FDA Warning Letters Shows Patient Safety Violations, Inadequate Record Keeping Common in Clinical Trial Concerns

2012 FDA Warning Letters: What Can Be Learned?

An analysis of the warning letters issued by the FDA to pharmaceutical manufacturers regarding misleading health outcomes claims.

FDA warning letters, known as Form FDA 483 is defined as

…a correspondence that notifies regulated industry about violations that FDA has documented during its inspections or investigations. Typically, a Warning Letter notifies a responsible individual or firm that the Agency considers one or more products, practices, processes, or other activities to be in violation of the Federal Food, Drug, and Cosmetic Act (the Act), its implementing regulations and other federal statutes. Warning Letters should only be issued for violations of regulatory significance, i.e., those that may actually lead to an enforcement action if the documented violations are not promptly and adequately corrected. A Warning Letter is one of the Agency’s principal means of achieving prompt voluntary compliance with the Act

They demand a prompt response from the organisation/company that receives such a letter. You can search the letters which are all published on the FDA website by clicking here.

 

Not everyone has or can afford Microsoft Office but there are plenty of free packages out there that do much the same as microsoft office and are similarly easy to use. You can get a free office suite of programs from many companies and organisations but one of my favourites is Open Office. Select the version open office for your system here:

https://www.openoffice.org/download/index.html

The website Pharmacology Corner looks to me to be a great resource for drug discovery, targets and receptors information. Well worth checking out to help with your studies and essays.

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The EudraLex V29  September 2014 has just been release. It is a substantial document but if you wanted to have a look at it you can download it from the link below. Warning the file size is 910mbs so it’s very large and will take a while to download on a slow connection.

http://ec.europa.eu/health/documents/eudralex/cd/index_en.htm

For individual sections of the Eudralex you can have a look at this link:

http://ec.europa.eu/health/documents/eudralex/index_en.htm

Please note this applies primarily to my own lectures and exams.

 

Below is a short video giving examples of some sampling plan questions.

 

For more information on sampling plans check out this post:

http://lecturehub.ie/?p=549

The file attached below contains sample calculations for questions on probability. Complete them if it helps you and send me your answers. Any questions please contact me.

Sample Calculations

According to RTE News

The Irish Medicines Board has confirmed that a number of batches of an anti-depressant drug being recalled by GlaxoSmithKline had been placed on the Irish market. The recall was ordered following a warning from the US Food and Drug Administration. It said the active ingredient for the drug, manufactured in Co Cork, may have been contaminated with a solvent from a pharmaceutical waste tank.

This website has some easy to understand information on sampling tables:

http://www.sofeast.com/aql-tables/

The first table gives us the code for the sample size based on our lot/batch size:

Sample size code

For thie table if we’re dealing with general inspection levels we can choose between:

a. Reduced (General inspection level 1)

b. Normal (General inspection level 2)

c. Tightened (General inspection level 3)

Once we have a code for our choice of inspection level we can then move to the second table to determine our sample size.

Sample size table

If for example our lot size is 1000 and our inspection level has been decided as level 2 (normal) then our code letter is “J”. This indicates a sample size for this lot as 80. If we have decided that our AQL (Acceptance Quality Level) level is 1 then we will accept the lot/batch if we have less then or equal to 2 rejects in the 80 sampled. If we have 3 rejects in the 80 sampled then we reject the lot/batch.

This is a really nice and easy paper to read that explains why we need statistics and data records not only in the scientific world but also in the pharmaceutical and medical device industry.

Twenty tips for interpreting scientific claims

science-20-rules-01

Image Courtesy: http://mkweb.bcgsc.ca/

Pharmaceutical and medical device manufacturers produce, retain, utilise and share vast amounts of documentation. Documentation (in the form of electronic records) relating but not limited to SOP’s, WI, data, QC results and reports. The system requires login details for each user and users are usually signed off after training or sections of the system. Their login details act as a digital or electronic signature. Once the user has logged in any information recorded is automatically linked to the logged in user. This allows the system to keep track of who is doing what. It is a fully traceable system. No two users have the same details and no one can use the system without authorisation and login details. The system will be backed up and usually off site so as to prevent any data loss in the event of a disaster. The records are essential in case of an issue arising that needs to be fully investigated. As documents (such as SOP’s) are revised and older ones removed from use, they are never destroyed but rather archived so as to provide a document history again in case of the need to return to older versions.

 

As mentioned in the notes, corruption in the pharmaceutical supply chain is a constant concern not only to the industries reputation but also to the health and safety of the patients using the products (drugs or devices). Up to 40 million prescriptions are filled with counterfeits each year in the United States. The article linked to below is from the economist and is about corruption and counterfeit drugs in the industry and it’s impact:

http://www.economist.com/node/21564546

This infograph below from create.org (The Centre for Responsible Enterprise And TradE) also illustrates where the vulnerabilities lie within the supply chain.

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The WHO uses survey’s to determine the risk or vulnerability a country or system is to corruption within the pharmaceutical industry. They us a combination of Klitgaard’s corruption formula and Cohen, Cercone and Macaya questionnaire’s which discussed in class.The link below describes the process in details

http://www.who.int/medicines/areas/policy/goodgovernance/AssessmentInstrumentMeastranspENG.PDF

You can look at the questions used in the surveys at the end of the document above (pages 109-154) to give you an idea of how the process works.

The link below is to a nice summary on the legal decision on Barr Laboratories practices with OOS results.

The main finding being that:

Barr’s practice of responding to an out-of-spec result by testing twice more and taking “best two out of three” is insupportable and unscientific, and is not GMP.

http://fdclaw.com/cases/gmp/

The link below is to the IPHA (Irish Pharmaceutical Healthcare Association) who represent the international research based pharmaceutical industry in Ireland.

http://www.ipha.ie/en/homepage.aspx

The pharmaceutical industry in Ireland today:

  • Currently generates over 50 percent of the country’s exports contributing to making Ireland the largest net exporter of medicines in the world.
  • Maintains substantial operations belonging to 9 of the top 10 companies in the world.
  • Manufactures 5 of the world’s top 12 medicines.
  • Directly employs over 24,500 people, over half of which are third level graduates.
  • Employs another 24,500 people in the provision services to the sector.
  • Has invested over €7 billion in Ireland over the decade and according to IDA Ireland the replacement value of the investment by the pharmaceutical sector in the Irish economy is over €40 billion.

The link below is to a nice presentation about the industry in Ireland today:

http://www.ipha.ie/GetAttachment.aspx?id=15cae642-5d04-41bb-a7ab-30e61c5407c9

 

 

Below are some examples of SOPs. SOP styles vary widely from company to company. What I want to see from an SOP were it to appear as a question is an SOP with the following headings: 1)Title, 2)Purpose, 3)Scope, 4)Equipment and Materials, 5)Procedure, 6) Special Notes. I would not tell you what SOP to write merely ask you to write an SOP of your choosing. It should be clear and precise and written as the notes on GMP & QA suggest. These headings are a minimum. I dont mind if you include extra headings but you’ll primarily be graded on the presence of these and the corresponding text that goes with them.

Examples of SOP’s (some of which are also on Moodle)

SOP Autoclave

SOP Template

SOP for Complaints Procedure

SOP for Change Control Procedure

The Orange Guide: Rules and Guidance for Pharmaceutical Manufacturers and Distributors (familiarly known as the Orange Guide) is an essential reference work for all those involved in the manufacture or distribution of medicines in or for Europe. It is compiled by the UK drug regulatory body, the MHRA, and brings together the European and UK guidance documents and information on legislation relating to the manufacture and distribution of medicines for human use. It therefore contains EU guidance on good manufacturing and good distribution practice along with relevant information on EU and UK legislation.

 

The Orange guide is not available for free access but a sample chapter on premises and equipment can be found here. A full list of its index is also available here.

The publication Approved Drug Products with Therapeutic Equivalence Evaluations (the List, commonly known as the Orange Book)  is a list that identifies drug products approved on the basis of safety and effectiveness by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act (the Act).

Did you know that when the first print edition of Approved Drug Products with Therapeutic Equivalence Evaluations was being prepared October 1980, staff members in the Office of Generic Drugs had to choose a color for the cover. The project manager suggested, “It’s almost Halloween. How about orange?” Before long, The Orange Book had become a popular short title for this important publication. Courtesy FDA

The downloadable Orange Book “list” can be found here:

http://www.fda.gov/drugs/informationondrugs/ucm129689.htm

The link below shows a specification sheet outlining an SOP on how to calibrate a pH meter. It includes information on the expected pH Buffer Values at Various Temperatures since pH is affected by temperature.

pH meter calibration

Here is a link on the FDA website of an example of a warning letter:

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2013/ucm369495.htm

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And some more info and FAQ’s related to FDA 483 forms and Warning Letters

http://en.wikipedia.org/wiki/Form_FDA_483

https://en.wikipedia.org/wiki/FDA_Warning_Letter

http://www.fda.gov/ICECI/EnforcementActions/ucm256377.htm