GMP & Quality Assurance

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

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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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

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 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

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/

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 link below is to the Documentation section (Chapter 4) of the EudraLex Guide: The Rules Governing Medicinal Products in the European Union.

http://ec.europa.eu/health/files/eudralex/vol-4/chapter4_01-2011_en.pdf

 

You might see Gantt charts mentioned throughout the notes. While not specifically part of our studies It is worth knowning what they are. A Gantt chart is a simply a type of bar chart that maps out a project timeline or schedule. Gantt charts illustrate the start and finish dates of different elements and what elements of a project can run together or after each other. It can also list information on milestones or major events/meetings. Below are some examples:

example gantt chart Gantt Swiftlight-Timeline-Example4

Below are links to actual product recalls by regulatory authorities illustrating the contents of a recall document.

FDA Recall Example

IMB Recall Example

I mentioned this to some of you before. This was a BBC documentary on how to build a jumbo jet engine and I thought it was very good at showing the level of QC that goes into the design, construction and operation of some products such as a jumbo jet engine. As part of its design the housing for the jet engine must remain intact and contain all parts of the engine in the event of a catastrophic event such as a bird strike. In order to prove it will the company (Rolls Royce) must build a fully workable jet engine and then destroy it (from 39mins 54secs). You can watch the full video below:

The documents below out line the Eudralex and FDA GMP guidelines for dealing with complaints and product recalls.

Eudralex Guide to Complaints Product Recall

FDA Guide to Complaints and Product Recall

According to the FDA guidelines an internal audit should cover the following topics:

FDA CFR Volume I – 4.14 Internal Audits

An internal audit procedure template can be found here:

FDA Audit Procedure Template

An example of an internal audit schedule can be found here:

FDA example of Audit Schedule Template

Before starting the audit you might send an audit questionnaire to the vendor/supplier to gain more information from them before beginning the audit. The link below contains an example questionnaire:

1. Vendor Audit Questionnaire

During the audit you can use a simple checklist to record information. The link below contains an example of a checklist

1. Audit Checklist

Finally once the audit is finished an audit report must be produced. Here are two examples of audit reports:

1. Sample Audit Report

2. EU final audit report template

A qualified person (QP) is a technical term used in European Union pharmaceutical regulation (and therefore Ireland). The regulations specify that no batch of medicinal product can be released for sale or supply prior to certification by a QP that the batch is in accordance with the relevant requirements. (EudraLex, Volume 4, Chapter 1). In the USA there is no specific requirement from the FDA for a person specifically called a “qualified person” but the FDA requires that a company selects someone who is qualified to be the person who signs off on batches.

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

According to the Annex 15 of the EU Guide to Good Manufacturing Practice:

Change Control: A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status of facilities, systems, equipment or processes. The intent is to determine the need for action that would ensure that the system is maintained in a validated state. (Annex 15, see chapter C.6.15.)

As we’ve discussed in class, some companies use change control when they’re bringing in a new piece of equipment/process where there has been no previous validation. Under the EU guidelines change control can only happen on validated systems. When starting a new process or bringing in new equipment you would normally look at risk assessment or impact analysis and some companies may call this change control. For the purposes of an exam if a question came up on explaining change control then I’m happy to accept either the EU definition alone or if you explain how your company uses change control I’ll accept this too once you also explain the EU’s definition. Any questions just drop me an email.

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

Below are links to documents and websites showing “some” of the regulations for GMP in relation to Premises and Equipment from the EU, WHO and FDA

EU guidelines for Premises and Equipment

FDA guidelines on GMP for Premises and Equipment (Filters)

WHO guidelines on GMP for Premises (Section 12) and Equipment (Section 13)

 

 

 

From January 1st 2014 the Irish Medicines Board (IMB) will be known as the Health Products Regulatory Authority (HPRA).

 

 

The link below is an example of a site master file (SMF).

Site_Master_File_

Here is some advice on drafting a SMF from the WHO:

http://apps.who.int/prequal/info_general/documents/TRS961/TRS961_Annex14.pdf

The following links are examples of quality policy documents outlining the objectives of the companies.

Example 1 Alcatel-Lucent Quality Policy

Example 2 Alpha Plus Quality Policy

Below is a link to a pdf of a table of contents from a Honda Supplier Quality Manual. It shows many of the components of a quality manual as outlined in class including:

  • Introduction and Company Profile.
  • Policy and Objectives
  • Definitions
  • Quality system which applies in the company
  • Organization
  • Authority and Responsibilities
  • Process Control
  • Inspection and Testing
  • Validation
  • Calibration
  • Records
  • Training
  • Product release
  • Non-conforming Items

Honda Supplier Quality Manual

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