The Big Red Biotech Blog

EMA proposes virus testing for food sector-derived trypsin used in drugmaking

The EMA says that food industry controls on porcine-trypsin do NOT guarantee that it is virus-free. The agency is therefore proposing new procedures for drug and vaccine makers who use it as part of their process.

EMA proposes virus testing for food sector-derived trypsin used in drugmaking.

This arises most recently from the rotavirus vaccine contamination event by porcine circoviruses that was ultimately traced to porcine trypsin used in its manufacture. Based on events like this, the EMA made new recommendations:

• Use only trypsin from glands from pigs that have appropriate official health certificates
• Test for specific viruses using both porcine and primate cell lines
• It advises use of two complementary virus reduction steps in processing -- e.g. low pH and irradiation

Under the guidelines proposed the drug or vaccine producer would have the responsibility to ensure proper testing (via its vendor if desired) and safety processing steps had been undertaken.

The EMA also noted that potential alternatives to trypsin could be used from recombinant sources or could be plant-derived (like TrypZean) saying ---- "the use of bacterial or plant derived recombinant trypsin minimizes in principle the risk for animal virus contamination and the application of such alternatives is therefore encouraged."

Posted by Bruce Lehr Mar 6th 2013.

Big Pharma Scramble for China Foothold

Fierce Biotech this morning reports on the top 10 Big Pharma companies investing in China.  Clearly, these companies are jockeying for position to be able to exploit commercial opportunities in the BIG Chinese market.  In many cases, these is seen as essential to future company growth and survival given some of the issues with patent cliffs, and stagnant growth in many of the traditional Western markets.

Pharma investments are aimed at gaining market access and in particular gaining face time with health budget decision makers.  Investment in China is certainly seen by the government to be a "good thing" and goes a long way toward establishing credibility. Hooking up with local drug companies and developers is a good way to enter the market.  Alliances with local players may ultimately be a necessity for the Western companies to crack this market -- and many have established early relationships accordingly.

This is interesting to me in that many of these same companies right now are trying to eliminate China-produced raw materials from their supply chains. Yet, if their goal is to crack the Chinese market and to partner with local developers and manufacturers to do so, then how can they eliminate Chinese suppliers in the long-term?  They can't.  You will want to source locally for manufacturing support -- maybe not some specialty items but bulk of raws will likely come from local sources.  The economic drivers and incentives are just too great in my view -- and local goverment will expect it.

So time is now to start qualifying the best local suppliers, and to educate and incentivize them to continually improve their quality systems in anticipation of them being integral to a long-term supply chain.  It only makes sense.

Posted by Bruce Lehr Nov 19th 2012

Sigma-Aldrich to Acquire BioReliance

Sigma-Aldrich will add BioReliance to its portfolio of products and services aimed at supporting the development of biological drugs.  The deal adds BioReliance's $110 M in revenues in the biopharm space and projected double digit growth for 2012 to Sigma's coffers for a cash price of $350 M.

Sigma-Aldrich to offer start to finish bio-testing thanks to BioReliance takeover.

The SAFC group within Sigma-Aldrich focuses on the supply of raw materials to make pharmaceuticals and biopharmaceuticals, does some process development, and offers contract manufacturing and testing services.  BioReliance's capabilities in biologics testing, specializes toxicology and in animal health testing will add to SAFC's portfolio.  In particular, SAFC will now be able to support testing of both raw materials and final product.

In the production of biological drugs, the combined companies can work together as well in areas like cell line development, banking and testing to support biologics processes -- as well as provide more extensive testing and characterization of final product produced in SAFC plants.  Plus with the burgeoning biosimilars area, the combined group will be able to collaborate in areas like glycoanalysis to support product comparability or "biosimilarity".

It's an exciting combination that may promote more of a "one-stop-shop" menu of services to existing clients. Said Sigma-Aldrich President and CEO, Rakesh Sachdev, "As the market continues its focus on biological drug development, our leadership in this area should enable us to build even better, more customer-specific solutions."

Download Press Release_BioReliance_010912[1]

 

Posted by Bruce Lehr Jan 10th 2012.

SAFC sets sights on a "proactive" supply chain management system

Ed Roullard, VP Marketing for SAFC on supply chain and quality management said, "After recent issues in supply chain management, the FDA has told customers they need to regulate and control their own supply chains. And what we have now is pharma companies asking every question it can ask which costs everyone time and money."

SAFC sets sights on a "proactive" supply chain management system.

SAFC has tried to adopt a pre-emptive stance by doing such things as removing animal derived components, performing risk assessments on chain partners, adding "layers of protection" through the production process rather than simply testing an end product. But, the industry still has a way to go.

Ideally, the industry will begin to work together to share audit results on supply chain partners -- and SAFC will play its part in helping to make it happen.

"The pharma industry should not be competing on supply chain and quality management, they should be working together," says Roullard.  Amen.

 

Posted by Bruce Lehr Sep 26th 2011.

 

Brazil & USP Ink Deals to Raise Quality Standards

In another example that recognizes the increasingly global nature of the pharmaceutical business, USP made several new agreements with entitites in Brazil to promote higher quality and increase the degree of regulatory harmonization.

Brazil & USP ink deals to up quality, harmonise standards.

The USP signed agreements with ANVISA, a Brazilian regulatory group, and with Sindusfarma, an industry group representing drug manufacturers that account for 85% of the country's sales.  Under their agreement, ANVISA and USP will develop joint education programs for drug formulators.

"In helping to ensure a high-quality supply of pharmaceutical products and ingredients in Brazil and throughout the world, Sindusfarma looks forward to a continued and strengthened working relatonship with USP," said Sindusfarma's executive vie president, Lauro Moretto.

And pharmaceutical industry globalization continues to march on.

 

 

 

 

Posted by Bruce Lehr Aug 23rd 2011.

Complex supply chain driving shift in analytical methods

As the pharmaceutical industry becomes increasingly global, so has its supply chain.  The complexity of the chain is such that more and more stringency and oversight is needed to ensure product safety and integrity.  Recent examples, including contaminated heparin, have pointed out this problem emphatically.

Complex supply chain driving shift in analytical methods.

As a result, companies and regulators are increasingly looking at more and better analytical methods for characterizing key raw materials used in the manufacture of pharmaceuticals.  This is one means (by no means the full solution) that can be used to better assure the safety of supply. This article describes how the heparin monograph and analytical methods have been upgraded in response to this issue by the FDA and USP working together.

Along this same light, I've written here often about SAFC's internal program to better characterize raw materials that it is supplying in its cell culture products for use by the biopharmaceutical industry in manufacturing of recombinant protein drugs. This is a program that has strongly resonated with the industry due to the issues described.  See here, here, here and here for more on this topic from this blog.

Posted by Bruce Lehr December 4th 2010.

Pharma Exec's Top Supply Chain Worries

The PharmaTech Talk blog summarizes a new report from PricewaterhouseCooper and Axendia entitled, Achieving Global Supply Chain Visibility, Control & Collaboration in Life Sciences: Business Imperative, Regulatory Necessity.

The groups surveyed 112 executives from pharma, medical device and biotechnology sectors.  Fifty-percent (50%) of respondents said the biggest area of risk was raw materials sourced outside the US, with sixty-one percent (61%) indicating contaminated or nonconforming raw materials was the top threat in the next 5 years.

Visibility into their suppliers supply chains is limited. Seventy-seven percent (77%) said period audits was their primary means of gaining this information. Only 25% said they shared best practices with suppliers, and a very tiny 3% have any real time data from the supply chain. This would seem to be an opportunity for suppliers to gain advantage by delivering against this need.

With regard to track and trace and serialization technologies, as a means to gain supply chain control, respondents said their current hurdles to implementing this technology are cost, difficulty of implementation; lack of standards, and lack of regulatory requirements and guidance.

As mentioned many times in this blog, SAFC instituted a raw material characterization program approximatley 2 years ago to enhance the analytical and biological characterization of raw materials used in industrial cell culture biomanufacturing and development. The program is clearly aimed at identifying problems with key raw materials that would affect product performance and to fix those issues to deliver increased product performance and consistency.

Posted by Bruce Lehr October 28th 2010.

More Raw Material Trouble in China

The PharmaTech Talk blog reports more trouble out of China with supplies of crospovidone. It seems the FDA is investigating one lot of Chinese supplied raw material for excessive amounts of peroxide - reportedly found to be 4 times theses maximum allowed level of 400 ppm as recommended in the monographs.

These peroxide levels are not inherently dangerous to human health directly - but as crospovidone is used ubiquitously in many drug formulas - there is fear that elevated peroxide levels could have adverse effects on shelf life of active ingredients resulting in loss of drug potency before expected.

If problems with this Chinese source material are confirmed, this will just be another black eye for raw material suppliers in this area of the world given previous problems with heparin and melamine. Go to the blog link above for further links to FDA site on this topic.

 

Also, you may be interested in searching this blog for addtional posts on the SAFC raw material characterization program. We have established enhanced analytical and biological testing regimes to better characterize all our raw materials going into cell culture medium - for example - that support biopharmaceutical manufacturing.  Examples are here, here and here - but there are more.  There are also links to a couple of interviews on supply chain integrity and supporting quality systems - one from me and one from our VP of Quality and Regulatory Affairs, Tom Beil.

 

 

Posted by Bruce Lehr October 23rd 2010.

Call Out for Two Sigma/SAFC Websites of Interest

I want to highlight a couple of websites that may be of interest to readers here. The first is called the Media Expert.

The Media Expert (ME^®) is a comprehensive source of information on cell culture media components and formulation:

• Provides reviews on all major components used in cell culture media
• From albumin to zinc
• Provides information on formulation strategies
• Primary functions for each component in cell culture applications

The Media Expert is also a problem solver:

• Discusses common symptoms seen in cell culture
• Suggests possible causes
• Provides guidance for relieving the symptoms observed

Examples include poor cell attachment, poor cell growth, and degraded cell products.  I urge anyone interested in cell culture Media to check it out.

The second site is our social media hub known as SAFCLive.com.  SAFCLive provides a place where you can share your views.  It also has a stream of updates on SAFC activity in the pharma and biopharma industry.  There are industry stories, links to various resources - like publication, regulatory or industry organization websites.  You can even see My most recent blog posts and access my Blog from the site.

 
Posted by Bruce Lehr October 16th 2010.

 

World Pharmacopeia Sing in Harmony?

The USP will host the 10th International Symposium on Pharmaceutical Reference Standards in Rockville, MD next week. The meeting will have representatives from China, Japan, Europe and North America in an open forum to discuss compendial issues.  The WHO also will be in attendance.

PharmTech Talk » Can Reference Standards Symposium Revitalize the Pharmacopeia?.

The goal is to increase harmonization across the globe. This year's agenda includes:

• Quality systems expectations
• Complying with global regulation
• Metrological guidance of reference standards
• Control strategies for drug product quality

There are growing concerns regarding the potential for drug ingredient contamination. This is a forum that could allow various global agencies to make sure they are on the same page with regard to regulations covering metal-impurity testing, water for injection production, and residual solvents.

As noted yesterday in a post about the IPC and the USP looking to become more aligned, harmonization is increasingly important to a global pharmaceutical industry.  Suppliers of raw materials operate globally but are often forced to adapt locally to test methods and SOPs.  Pharmaceutical manufacturers similarly have to adapt test methods and licensing files to local requirements.  These steps add a lot of costs that don't add a lot of value and are effectively passed to the patients and healthcare system. Harmonization not only clarifies the rules for all players, but decreases costs and increases efficiencies.

We'll see how the 10th Conference makes out with regard to these outputs.

Posted by Bruce Lehr September 8th 2010.

IPC Seeks to Match USP Standards

The Indian Pharmacopoeia Commission (IPC) says it wants to follow standards set by the Pharmacopoeial Discussion Group (PDG). In a meeting last week, the IPC indicated it want to come into alignment with the USP, European and Japanese Pharmacopoeia standards.

IPC plans to collaborate with USP, who will in turn provide IPC with USP reference standards. IPC also plans to pick up USP convention nomenclature in labelling.  The IPC also invited the USP to the 13th annual Indain Drug Manufacturing Association - Pharmaceutical Analysts Convention in Mumbai next month. See in-Pharma Technologist.com.

Harmonization is increasingly important to a global pharmaceutical industry.  Suppliers of raw materials operate globally but are often forced to adapt locally to test methods and SOPs.  Pharmaceutical manufacturers similarly have to adapt test methods and licensing files to local requirements.  These steps add a lot of costs that don't add a lot of value and are effectively passed to the patients and healthcare system. Harmonization not only clarifies the rules for all players, but decreases costs and increases efficiencies.

If interested in this topic, you may also wish to refer to this talk by Dr. R. Ramakrishna, Dy.Drugs Controller India, entitlted "Advances in Indian Medicines Regulation with Special Focus on Pharmacopoeial Standards"

Posted by Bruce Lehr September 7th 2010.

 

Congress Moves Again on Drug Safety and Quality

Drug safety is an important enough topic that I am going to provide another post from the PharmaTech Talk blog that addresses the new Senate legislation proposed to enhance drug safety. 

PharmTech Talk » Congress Moves Again on Drug Safety and Quality.

The blog post provides links to the bill, Drug Safety and Accountability Act of 2010, as well as to statements from interested parties like the Society for Chemical Manufacturers and Affiliates (SOCMA), the Bulk Pharmaceuticals Task Force (BPTF), and the Pharmaceutical Research and Manufacturers of America (PhRMA).  SOCMA and the BPTF supported the proposed legislation effusively.  PhRMA was a bit more reserved in its response, noting that GMP requirements are followed now whereever a drug is manufactured for the US market (or at least are supposed to be).

Posted by Bruce Lehr August 4th 2010.

Senate bill would bolster drug safety requirements

Drug safety is a hot topic again.  Sen. Bennet introduced legislation this week that would enhance the FDAs enforcement powers and hold drug companies more accountable for products that they sell.

Senate bill would bolster drug safety requirements - The Hill's Healthwatch.

The bill would update FDA data systems for tracking drugs globally, force drug manufacturers to document ingredients in its supply chain, grant FDA subpoena power, and empower the FDA to order recalls for safety reasons.

This comes in the wake of a record number 1742 recalls in 2010 -- a 400 percent increase over 2008. You can read more related to the topic of supply chain and risk management in Changing the Concept of Quality at SAFCLive.com. 

Posted by Bruce Lehr August 4th 2010.

Changing the Concept of Quality

 

 

Here's an interview from SAFC's own Tom Beil, Vice President of Quality and Regulatory Affairs.  Tom speaks to the changing quality needs in the biopharma/pharma space - particularly with respect to complexity of managing supply chain and risk.

Follow the link to Tom's interview with Hilary Ayshford, Editor of Manufacturing Chemist on SAFCLive.com.

Posted by Bruce Lehr August 4th 2010.

 

SAFC's - Enhanced Quality Program (EQP)

I've written quite a number of posts on this blog about the increasing need in the bio/pharma industry to have better characterization, control and traceability on raw materials being used in the process of producing drugs.  The regulatory bodies around the world - FDA, EMEA, etc - clearly are placing more and more emphasis on this need.  Quality is paramount in the production of safe and efficacious products.  The very public incidents of quality lapses with major manufacturers only serves to heighten this concern - whether the incident stem from a China, US or EU based manufacturer. 

Several previous posts highlighted SAFC's new raw material characterization program aimed at better characterizing and qualifying materials used in cell culture based manufacturing of biopharmaceuticals. You can review these here, here, here, here and here. (Told you, I've posted about this before).  You can also refer to the popular Raw Material Detective series of posts for some real life examples.

Now, SAFC introduces its Enhanced Quality Program (EQP^SM).  The EQP is designed to transparently show customers the Quality levels associated with the large number of SAFC products that could be used in manufacturing.  This is meant to aid customers in choosing the RIGHT product for their application - as quality needs are application specific in many instances.  EQP levels differ in their degree of quality certification, documentation and change control. EQP products fulfill a range of needs from industrial applications through the more heightened controls of the biopharma and pharma industry.  Premium, Elite and cGMP levels exist within EQP.

EQP is consistent with ISO requirements and meets international standards for multiple industries. One of the significant features of the EQP is the Change Control Notification (CCN) program. Customers may subscribe to this program at www.safcglobal.com/ccn.  On our website, customers can also search on CAS numbers to determine if we have a product that meets your Quality needs.  If not?  Customers may request an upgraded product and our compliance specialists will be able to determine through consultation whether we can accomodate that change.

For more information, refer to the links in this post - and on overview can be found on this attached flyer.

Download MOU_EQP Flyer_LR

 

 

Posted by Bruce Lehr July 24th 2010.

Chemistry World Interview - Raw Materials & Supply Chain Integrity

I actually got interviewed in an article just published online with Chemistry World, a publication of the Royal Society of Chemistry.  It is a piece detailing some of the recent problems seen with pharmaceuticals resulting in recalls or low product availability.  Most of these resulted from issues with raw materials and in some cases may have been compounded by the manufacuring and quality system lapses too.

My comments have to do with the integrity of the supply chain and the need to really interrogate the whole system - including stepping up with enhanced understanding of your raw materials and their suppliers.  This is in line with my Raw Materials Detective series and our the SAFC Raw Material Characterization initiative.

 

 

Posted by Bruce Lehr June 23rd 2010.  

Melamine testing of Excipients Webinar June 29th

Angie Drakulich in the PharmaTech Talk blog announced that Pharmaceutical Technology will be sponsoring a webinar on June 29th that will address topic of melamine screening - particularly for pharmaceutical excipients. 

Presenters for the webinar include the FDA's Steven Wolfgang, Recall & Shortages Branch, FDA's Brian Hasselbalch, Division of Manufacturing and Product Quality, and Dave Schoneker, IPEC. 

The seminar will touch on recent movements with melamine testing and screening.  USP has been working with a coalition consisting of IPEC, PhRMA, GPhA, CHPA, and SOCMA to look a monographs for melamine testing. USP has also been exploring use of infrared spectroscopy and gel permeation chromatography in screening excipients - which should help melamine detection.

See previous Big Red Biotech Blog post for SAFC approach to melamine screening and risk assessment.

Posted by Bruce Lehr June 19th 2010.  

The Raw Material Detectives - Case #2 - The Fouled Filters Part 2

It was now an overcast day as we return to our story.

What next? The RMDs reviewed all the lot numbers of the PVA from above average, average and below average filtering lots of customer media at large scale. This review indicated a temporal correlation between good and poor filtering lots of PVA used in the media. It became apparent that lots of PVA manufactured prior to Feb 2007 on average filtered better than subsequent lots of material.

Turbidity Assay

The Raw Material Detectives decided to look at selected PVA lots along the time continuum, with known good or poor filterability, in a turbidity assay. In this assay, 6 grams of PVA were dissolved in 100 ml of water with stirring for 60 minutes. Turbidity was measured using a Hach 2100N Turbidimeter and reported in NTU.

Data for the turbidity assay appears in the Table 1 below. PVA lots are arranged chronologically by date of manufacture. Results show a strong correlation between turbidity and filterability. Lots with turbidity below 10 NTU filter above average.  Lots with turbidity measurments greater than 20 NTU filter below average.

In the Table the lot numbers have been altered to protect the innocent. The altered lot numbers depict month and year of manufacture. Note, two lots were used in multiple batches of medium and in some cases exhibited above average filtering characteristics - even with the high turbidity number.

 Table 1.

PVA Lot	Turbidity (NTU)	Filterability
Lot 08-2005	4.9	Above Avg.
Lot 09-2005	4.7	Above Avg
Lot 04-2006	3.5	Above Avg
Lot 06-2006	2.8	Above Avg
Lot 01-2007	9.6	Above Avg
Lot 02-2007	4.1	Above Avg
Lot 05-2007	25.0	Below Avg.
Lot 02-2008	14.9	Below Avg
Lot 02-2008 (2)	28.4	Below & Above Avg
Lot 04-2008	32.0	Below & Above Avg
Lot 01-2009	36.5	Below Avg
Lot 05-2009	130	Below Avg
Lot 07-2009	26.9	Below Avg

The RMDs had some evidence to support their hypothesis that a change occured in the manufacturing process after Feb 2007 but wanted more.

Pellet Analysis

The PVA lots hydrated at 6% for the turbidity assay were placed in a centrifuge at 3200 rpm.  The pellet was dried and weighed. The percentage of PVA in the pellet was calculated. The correlation was high between PVA in the pellet and the turbidity values.  Data from 3 of the above lots is shown below in Table 2.

Table 2.

PVA Lot	Turbidity (NTU)	% PVA in Pellet
Lot 01-2007	10	1.8
Lot 01-2009	47	9.5
Lot 05-2009	173	18.5

Enough already! Haven't we shown that the PVA is the issue?  It wasn't enough for the Raw Material Detectives. They needed to know why?

Hydrolysis & MW Determination

It was time to analyze the insoluble material in the pellets. The pellets and the supernatants from the above experiment were sent to Chemir Analytical Services for NMR, DSC and GPC (see previous post for more info).  The data is summarized below in Table 3.

Table 3.

PVA Lot	Sample	% Hydrolysis	Tm C	MW (Da)
Lot 01-2007	Pellet	86	192	13,374
Lot 01-2007	Supernatant	84	193	11,436
Lot 01-2009	Pellet	95	197	20,906
Lot 01-2009	Supernatant	83	192	10,479
Lot 01-2009	Pellet	91	216	21,663
Lot 01-2009	Supernatant	83	196	11,440
Lot 05-2009	Pellet	87	190	20,687
Lot 05-2009	Supernatant	84	189	11,965

*Two different batches of lot 01-2009 were sent to Chemir for analysis

The % PVA hydrolysis seen in the pellets was higher than seen in the supernatants. All of the % hydrolysis figures for both the pellets and the supernatants fell outside the specification range of 87-89%. But, the mix apparently met the release specification.

The MW's in the supernatants were lower with a primary peak around 11,000 Da.  The pellets were of much higher MW with a primary peak around 21,000 Da.  The melting point data did not really show a difference except with one of the pellets in the first 01-2009 lot.  We appear to have two subpopulations of PVA.

Smoking Gun Test

The Raw Material Detectives hypothesize that the increased insoluble material found in lots post Feb 2007 resulted in lower filterability -- and set out to reproduce it.

The RMD compared customer CHO media prepared with PVA as normal with media prepared with PVA after the insoluble material had first been removed. Data appears below in Table 4 for the 3 lots previously described. 

Table 4.  

PVA Lot	Untreated PVA (Vmax L/m2)	PVA Treated Supernatant (Vmax L/m2)
Lot 01-2007	624	1120
Lot 01-2009	218	834
Lot 05-2009	185	859

Thus removal of the insoluble material from the raw PVA resulted in higher filterability. The insoluble material is a subpopulation within the PVA with a higher MW and a greater percentage of hydrolysis. The Raw Material Detectives have identified this as the root cause of the filtration problem.

The Smoking Gun test confirms (as if you are a scientist - you perhaps prefer application of Koch's Postulate).

 

Acknowledgement: Raw Material Detectives Mike Wathen (old guy pictured center), Steve Wilson, Ben Cutak, Jodi Zobrist (pictured front with mustache) of SAFC Cell Science & Development and Analytical Research & Development groups.

Posted by Bruce Lehr June 14th 2010.

 

 

Raw Material Detectives - Case #2 - The Fouled Filters Part 1

It was a dark and gloomy night (just like last time).

This time two customers contacted the Global Technical Service (GTS) group with complaints of poor filterability of their lastest batches of a custom serum-free CHO medium, being used in large scale production of a commercial biopharmaceutical.  This formulation contained about 70 components including soy hydrolysate.  We put in a call to the Raw Material Detectives (RMD).

A review of the raw material lot numbers, used in the medium, by the GTS staff identified an association with a specific lot number of polyvinyl alcohol (PVA) CAS 9002-89-5 and poor filtering lots of medium. Thus a clue!  The Raw Material Detectives started with the PVA vendor.

Editor's Note: PVA is used primarily in industries like food, paper, adhesives and textiles. Cell culture is a very minor use application by comparison -- i.e. and therefore has reduced influence on the manufacturer/ supplier. PVA is produced by the polymerization of vinyl acetate to produce polyvinyl acetate. This is then hydrolyzed with sodium hydroxide to yield PVA.  Possible impurities in PVA would include sodium acetate, methanol, and methyl acetate. PVA should be readily soluble in water but requires heating. Degreee of hydrolysis , molecular weight, particle size distribution, and particle crystalline structure all affect solubility. Optimal solubility occurs at 87-89% hydrolysis, a fine particle size (< 80 mesh), 3.5-4.5 cps viscosity with a 4% solution at 20 C.

Vendor PVA lots were evaluated for D90 particle size, viscosity of 4% solution, and percent hydrolysis of PVA to look for correlation with customer poor filterability results. There was no obvious correlation.

Vmax Assay

SAFC worked with its customers to develop a scaled down Vmax assay that correlated with the filter difficulties seen at large scale. The following reference was developed.

• Vmax <1000 L/m² were correlated with below average filterability
• Vmax >2000 L/m² were correlated with above average filterability
• Vmax 1000-2000 L/m² generally were above average but not 100%

Based on the above assay, it was decided to to analytically characterize multiple PVA lots with different filterability results in an attempt to explain the poor filtration characteristics.

Analytical Testing

PVA powders associated with know above and below average filtering lots at large scale were sent to Chemir Analytical Services (Maryland Heights, MO) for the following tests:

• Gel permeation chromatography - compares MW properties
• Glass capillary viscometry (GCV) - compares intrinsic viscosities
• Fourier transformation infrared spectroscopy (FTIR) - compares base chemistry
• Proton nuclear magnetic resonance spectroscopy (¹H-NMR) - compares backbone chemistries
• Differential scanning calorimetry (DSC) - compares thermal properties
• X-ray particle diffraction (XRPD) - compares crystalline structures
• Laser diffraction - gives particle size determination

Four lots were sent for analysis from the current vendor - 4 above average filtering lots and 4 below average filtering lots. Additionally, the Raw Material Detectives came up with 2 addtional lots from 2 addtional vendors to also test.

Pretty slick set of analytical assays - huh? Unfortunately, there were no significant differences in the physical properties of the various PVA lots tested that were identified by any of these seven assays. WOW!  Time to quit? Never. The Raw Material Detectives always get their Man (so to speak). Read the next post for the Rest of the Story.

 

Posted by Bruce Lehr June 14th 2010.

Too Much Heavy Metal Raises Concerns

Your Mom and Dad always told you that too much Heavy Metal was bad for you.

Now the PharmTech Talk blog is raising the issue too. Dangerous Heavy Metal contamination of raw materials -- and worse final products like dietary supplements, food and drugs -- have become increasingly common. This is much to the consternation of regulators, producers and consumers.

In partial response, several groups responsible for setting standards for heavy metal testing are working on new guidelines. The public comments on USP's new elemental impurities chapters, which update testing methods and limits for lead, cadmium, arsenic and mercury - the "big four" - were due April 15th.

And ICH's harmonization work on this issue is getting started this month in Estonia. The FDA's Joshua Sharfstein also recently testified before a Senate Judiciary committee -- looking into the regulation of food and dietary supplement safety -- and focused many of his comments on heavy metal levels.

As Angie Drakulich stated in her blog post, "Let's hope that between USP, ICH and Congress some progress can be made to keep consumer products free of dangerous levels of heavy metals in the long term."

A PLUG FOR HEAVY METALS - Pharmaceutical Technology is hosting a free webinar on heavy metals on Monday June 14th and Thursday June 17th 2010.  You can tune in here.

Posted by Bruce Lehr June 5th 2010.  

Greater Regulation of Excipients Only Matter of Time?

As posted in the PharmTech Talk blog, there is a good liklihood that the FDA will continue to raise the bar on the quality requirements associated with the manufacture and supply of excipients.  Recent issues with heparin, melamine and now final products Tylenol, Motrin and Zyrtec all but assure this will occur.

  Speakers at this year's IPEC meetings in Puerto Rico advocated that the time is now for us to really get into the details of our supply chain.  Just seeing a CoA, the label marked USP, an ID test result, and an audit are not enough. It is important to understand everything about it.

Speakers from IPEA and from RX-360 also said it is well past time for companies to begin sharing results of supplier audits -- particularly for excipients. They noted that Congress is now asking tough questions about why excipients are NOTaudited like API suppliers. It can be expected that the public servants (& public) and the FDA will require much more transparency in the supply chain - and the time has arrived for sharing audit information.

Again, this greater emphasis on knowing what is in your raw materials and how these will effect your process & ultimately your product is the essence of our Raw Material Characterization Intitiative. I would strongly support the notion of shared audits in addition to enhanced selection and testing of all key raw materials.

Posted by Bruce Lehr May 9th 2010.

PCV Testing Mini-Primer - GSK & Merck Rotavirus Contamination

Within the past 4-6 weeks, both GSK and Merck have reported finding fragments of the PCV virus in their rotavirus vaccines - Rotarix and Rotateg respectively.  As a result, my colleague Misa Gray wrote a mini-primer on PCV testing in raw materials.  I have extracted a portion that talks about the use of PCR for screening. 

Porcine circovirus (PCV) is a member of the family, Circoviridae.  it is a single-stranded, non-enveloped DNA virus. There are two strains PCV1 and PCV2.  PCV1 is not known to cause any disease in pigs, while PCV2 does cause a disease known as Postweaning Multisystemic Wasting Syndrome (PMWS).

Photo courtesy Dr. Stewart McNulty.

The FDA suspended Rotarix usage on March 22,2010 due to finding PCV1 DNA in the vaccine. GSK confirmed the presence of the virus in Rotarix. Trypsin was a suspected possible source of the virus (unconfirmed).  The source of the PCV remains under investigation by GSK and the FDA.

Raw materials, like trypsin, could be assessed for PCV presence by PCR testing assuming one can get a reasonable DNA preparation. Nested PCR (two sets of primers) could be utlized in cases where inhibiting materials might be present in the raw material sample. Multi-plex PCR ca nbe applied to test both for PCV1 and PCV2 simultaneously - this of course requires two independent set of primers.

Several commercial labs offer PCV2 screening - presumably due to its potential impact on animal health and the food chain. PCV1 is not normally offered by these same commercial  test labs. Since the PCV1 sequence has been publoished and is available in GenBank, we believe that it would be relatively straightforward to develop a screening assay.

For more on PCV, see the FDA site.

FDA and USP to Hook Up on Monographs (& such)

The PharmaTech Talk blog recently had an interesting post on the FDA's plans to have greater collaboration with USP.  FDA Commissioner, Margaret Hamburg, made these comments at the most recent USP Convention.

Commissioner Hamburg stated 3 objectives for the collaboration between the two bodies:

"First, Reference Standard Candidate Assessments will test standard candidate materials that are controlled substances.

Second, to combat economic adulteration, FDA and USP will exchange information on hand-held device applications designed to screen drugs for adulteration or contamination and will explore ways to integrate the requirements of those new technologies into USP’s documentary standards.

And third, FDA will assist in the development and modernization of USP monographs providing enhanced tests and assays to better assess and characterize drug ingredients and products."

This looks like a good approach to me.  I like the agency's new priority toward collaboration with outside experts.  This willingness to collaborate actively with USP seems similar to the FDA's earlier announcement this year that it would seek more active discussions with experts within the NIH to help speed drug application reviews.  This seems like a common sense approach to combine expertise from two sources to get a more wholistic picture and better result. 

With the drug adulteration issues that have arisen in China, and elsewhere, in past couple of years, it makes sense to tap and share expertise to use resources better and to institute best practices wherever possible. I like the USP collaboration's emphasis in looking at hand held technology to better detect contamination or adulteration.  Certainly, there is always room to look at imporving the science and analytical techniques spelled out in the monographs - there is more rapid evolution in testing and a greater need to stay current to meet the global regulatory challenges.  Especially, with the vast increase in volumes, shipments and nations involved in the supply chain.

This move is consistent with what our customers have spoken to us about in regard to improving testing around raw materials used in biopharmaceutical processing. Effectively the 3 FDA areas of emphasis with USP, will help to improve raw material characterization, and will do so in way that is relevant to the end users intended applications.  This will also be in alignment with the regulatory process.  This can only help move us toward a more secure global supply chain with more harmonized criteria for assessing quality.  This should lead to safer and better raw materials with consequent better final drugs coming out of these processes. 

I applaud this idea.  I'd like to see it move rapidly toward collaboration and implementation.  There may also be an opportunity here to tap into private company expertise and subject matter experts.  This could build upon the planned FDA-USP collaboration and go even further to incorporate testing standards, technologies and methods that are especially relevant to the industries and supply chains being regulated.

Posted by Bruce Lehr April 30th 2010.

Raw Material Detectives - Case #1 The Crystal Shift

 It was a dark and gloomy night.

Our Customer contacted the Global Technical Service (GTS) group with complaints of poor product performance. The GTS squad logged the report into the complaint handling system. 

The customer, a large, US-based biopharmaceutical company, reported that they were having problems with their custom CHO medium - and were observing growth and productivity fluctuations from lot to lot within their commercial process.  

An investigation began with GTS and quality assurance in a cross functional team that included members from supply chain management (SCM) and cell sciences and development (R&D).  A review of batch records listing raw material lots and vendors in the batches of media narrowed the list of potential culprits to 6 raw materials.

After extensive collaborative trouble-shooting, the Customer and GTS concluded that there likely was a problem with the L-tyrosine from a specific vendor that was included in the formulation.  Suspect was L-tyrosine 2Na H₂O.

The Investigative Team lined up 3 lots of L-tyrosine 2Na H₂O from 3 vendors for interrogation.  Vendor 1 was suspected as the supplier of the problematic material.  Vendor 2 and 3 were alternative qualified vendors for our line up.  We also included a positive control. CSD began its testing.

Analytical Testing

The suspect lot of L-tyrosine was tested side by side with lots from two other qualified vendors via several analytical methods.  The testing was performed to assure product identity and to allow the detection of impurities.

Reverse phase-HPLC (RP-HPLC)

Size-exclusion chromatography (SEC)

Ultra-performance LC-MS (UPLC-MS)

No significant differences were detected between the suspect amino acid, comparison vendor samples and controls via these methods.  No obvious impurities were detected.

Batch Record - Process Review

The manufacturing process flow diagrams were examined from the 3 vendors - suspect and alternatives.    Our first important clue - there was 1 process step difference from the others with the suspect vendor.

The Investigative Team decided to perform biological testing between the 3 different vendors to see if the suspect vendor's material would show biological variance.

Biological Testing

CSD tested 3 lots of L-tyrosine 2Na H₂0 from each of the 3 vendors in CHO-GS cells producing a control MAb.  CSD plotted growth curves and measured MAb productivity.

Cell growth curves generated with lots 1 & 2 of L-tyrosine from Vendor 1 at best reached only 88-90% of the average peak cell density seen for Vendors 2 & 3.  The worst performing lot 3 from Vendor 1 only reached 55% of the peak cell density seen for Vendors 2 & 3, and thus was also signifcantly worse performing than lots 1 & 2 from same suspect Vendor 1.

Download Tyrosine Cell Culture Data

Similarly, IgG productivity of CHO-GS cultures grown on medium containing suspect Vendor 1 lots of tyrosine was 12-63% lower than cultures grown on medium incorporating L-tyrosine from Vendors 2 & 3.

Download Tyrosine Productivity Data

Filtration Studies

Since the biological variance of the suspect material had been confirmed, one logical explanaton for the poor performance was a solubility problem with the L-tyrosine from Vendor 1 as compared to the other two vendors.  

The Investigative Team decided to run filtration studies.  Lots of L-tyrosine from the various vendors were filtered and the post-filtration amino acid concentration was calculated versus the expected yield. Vendor 1 material did not filter as well.  When cells were grown in medium formulated with different lots of L-tyrosine from the 3 vendors, there was a direct correlation found between the amino acid concentration remaining and the productivity titers in cell culture assays. The suspect L-tyrosine was not making it through the filters.

Download Tyrosine Filtration Data

Physical Property Analysis

SAFC owns a company called Pharmorphix that provides expert solid state chemistry services and specializes in pharmaceutics. CSD decided to have them analyze 3 lots of the L-tyrosine 2Na H₂O from suspect Vendor 1(bad lots) and Vendor 2 (good lots).

SAFC's Pharmorphix group performed 3 different analytical techniques:

X-ray particle diffraction (XRPD) to determine crystal structure.

Differential scanning chromatography (DSC) to determine melting points of the crystals.

Ion chromatography to allow quantitation of the Na⁺ ions.

Results for the XRPD analysis are shown below.  These results reveal there were distinct crystal forms between lots from Vendor 1 and Vendor 2.  What's more? Vendor 1 had different crystal forms between its own lots and multiple crystal forms existed in 1 lot - the very poor performing lot 3.  DSC also pointed to the suspect L-tyrosine having melting points that varied from the "good lots" and exhibited multiple melting points within the population of 3 suspect Vendor 1 lots. Suspect 1 was different.

Download Tyrosine XRPD Data

Case Conclusion

Evidence revealed differences in crystal structure between good lots of tyrosine and suspect Vendor 1 bad lots of tyrosine.  These structure differences likely led to the poorer solubility characteristics of Vendor 1 material. This in turn led to poorer filterability and lower concetrations of Vendor 1 tyrosine in the final medium post-filtration.  This resulted in the poorer growth and productivity observed in the CHO GS cells.

Why the difference in crystal structure?  Recall the batch record review.  Suspect Vendor 1 was using spray drying to prepare its final tyrosine product.  Vendors 2 & 3 were using tray drying.  We believe this led to the variablity in crystal structure seen with the Vendor 1 material. 

Corrective Action

SAFC Supply Chain Management and Quality Assurance shared the analytical findings of the CSD team with Vendor 1.  Vendor 1 was busted.

Vendor 1 at present has been removed as a Qualified Vendor of L-tyrosine to SAFC. Vendor 1 would have to go back through a qualification process with at least 3 lots of new material before it could potentially be qualified again. 

Case File: 04272010-01

Raw Material Detectives Case No. 1

Suspect: L-tyrosine 2Na H₂O

Charge: Poor solubility and decreased product performance

MO: Crystal form change due to spray drying process

Solution: Use qualified vendor 2 or 3; Suspect Vendor 1 disqualified pending results of any future requalification effort

Case Disposition: Case Closed with final vendor notification of investigation. Results are Crystal Clear.

Posted by Bruce Lehr April 27th 2010

 

 

 

 

Raw Material Detectives - coming this week - Case #1

Visit the Big Red Biotech Blog this week for the first installment of the Raw Material Detectives.

This series is devoted to the mysterious misbehavior of raw materials in biopharmaceutical processing.

The investigation of the mystery.  And the solution to the Case.

Case #1 - The Crystal Shift 

The Raw Material Detectives are always traceable to probable cause. They have their thinking CAPAs on! 

Posted by Bruce Lehr April 25th 2010.