Pharma Bio World

Performance of Aluminium Based Packaging Materials Related to the Structure
Dr. E. Pasbrig GM Development and Technology ACG Pharmapack

Cold form laminate in India normally has aluminium thickness of 50μm. Internationally, 45 μm is used for packaging of standard products. If a higher dent resistant of cavity is needed, the thickness of aluminium will be 60 μm.

Difference of 5 μm in thickness does not provide a better dent resistant, as shown in next table.

CFF	Stifness (Nmm)
25-45-60	1.13
25-50-60	1.14
25-60-60	2.12

oPA-Al-PVC

Formability of the laminate with 50 μm aluminium is not increased compared to the standard laminate with 45 μm Al. Use of laminate with 60 mm aluminium provides a slightly better formability and more consistent forming results related to pinholes (higher cost).

Reduction of aluminium thickness by 5μm for a cold form blister with dimension of 120 x 55 mm results in 18 kg material saving for packing 2 Lakh of blister.

Aluminium thickness (μm)	45	50
1 reel (20 kg) in m2	84.4	79.8
Running meter (width 200 mm)	422	399
2 blister/cycle	844	798
2 lac blister (1320 sqm) (kg)	313	331
Saving (kg)	18
Approximately Saving (INR)	6311

40 cycle/min, blister 120 x 55 mm

Possible savings over a year, depending how many shifts per day are done, are in the range of 22 to 89 Lakh.

	kg	INR (Lakh)
1 shift/day	6552	22.3
2 shifts/day	13104	44.6
4 shifts/day	26208	89.2

The example is showing, that CFF with 50 μm does not have an advantage in performance, needed higher amount of material by area and more frequent changes of reels during production.

Lid Foil, Aluminium Thickness 25 μm and 20 μm

Similar result we get for the change of 25 μm to 20 μm aluminium thickness for lid foil. Beside the USA market, all other countries use a thickness of 20μm, and Japan uses even 3 μm less.

For aluminium foil produced in Europe, the maximum amount of pinholes per m2 with 0.5, respective 0.4 for 25 μm are similar and do not influence the barrier properties of the sealed blister.

Savings of material for the lid foil, as mentioned in the following table, are up to 21.8 percent.

Al	HSL	Lacquer	wgt.	Yield	Saving
54.0	7	1	62.0	16.1	21.80%
67.5	7	1	75.5	13.2

For a production of blister (60 x 95 mm; 4 blister/cycle; 40 cycle/min; weight of reel = 14 kg) switching from 25 to 20 μm, produces 7040 blisters more, with 20 μm foil. In addition, time until reel needs to be changed is increased by 44 min.

Figure 1: Performance of Aluminium Based Packaging Materials Related to the Structure

Cycle per reel (14 kg)

Thickness (μm)	20	25
14 kg = m2	225.8	185.4
Cycle/14 kg	9956	8176

Running time per reel

Thickness (μm)	20	25
Production time (min)	249	205
Difference (min)	44

Related to seal strength, heat resistance, abrasion of printing ink, there is no di erence between the 20 and 25 μm foil used for converting.

Burst pressure is increasing with the thickness of the foil. With this push through, force is increasing too. It is dificult to push a hart gelatine capsule through 25 μm foil without denting/pressing the capsule.

Reduction of Packaging Material -Strip Pack - CFF - Tropical Blister

Moisture sensitive products packed in strip pack are as well protected as in CFF. If sealing layer of CFF has to be identical as strip pack, LDPE or HDPE can be used. As sealing layer of lid foil an extrusion coating of LDPE on 20μm aluminium is used.

Comparison of strip pack and CFF highlights the main points as;

more packaging material has to be used.
product is in direct contact with sealing roller (hard gelatine capsule can stick on PE) and temperature sensitive products cannot be packed.

Calculations to compare size of pack have shown, that with usage of CFF, 30% to 70% reduction is possible, depending on product geometry. If tropical blister is used, further saving is possible. Reduction in size is not identical with saving of cost. But if all points are taken, every example shows savings;

production time and output
lower weight
smaller folding carton
more blister in shipper
lower cost for logistics

These calculations come into play if a customer expresses an interest to switch from strip pack to CFF or tropical blister.

Lid PE

Sealing layer of lid foil (push through) for sealing to CFF with polyethylene (LDPE, HDPE, CFF with desiccant) is produced by extrusion coating. To get su cient adhesion to the aluminium surface a primer (lacquer ) is used between aluminium and PE. Because of this sealing, the layer related to lid foil is double in thickness compared with lacquer of 7 g/m2 where double amount of humidity and oxygen is migrating through it into the cavity.

We were able to develop a push through foil with a lacquer in sealing to polyethylene with 5 or 7 g/m2, depending on customer requests. Not only is the cost less, but more importantly, the cross migration is reduced by 50 percent. This lid foil is on the market already and replacing the material with extruded LDPE.

Summary

Use of CFF with aluminium of 50 μm compared with 45 μm does not have any advantage related to performance; costis higher related to area.
Switching of lid foil with 25 μm aluminium to 20 μm provides an advantage related to cost and change time of a reel.
Change from strip pack to CFF can reduce pack size by 30 - 70 percent.
Lid foil for sealing to polyethylene with a lacquer can replace the currently used lid foil with LDPE extrusion coating. It provides cost advantage and better barrier related to cross di usion of a CFF blister.
If barrier layer of thermo form films are on inner side barrier properties after forming is increased by 11 - 15 percent.
ACG Pharmapack is offering a unique service to the pharmaceutical industry related to thermo forming, cold forming and sealing

"Drug Abuse Liability Study: A Category Analysis"
Siddhartha Shaurabh, Lead Analyst with Beroe Inc	Drug Abuse Liability (DAL) assessment evaluates the likelihood of drug abuse or dependence on the prescribed drug and hence forms the core for safety pharmacology study in developing drugs for central nervous system (CNS). The drug abuse liability testing market is largely driven by global CNS therapeutics market which represents around 17 per cent of drugs in clinical trials in 2013. Considering drug abuse a major health concern, DAL, which was earlier confined to clinical phase, has been incorporated in pre-clinical stage by the regulatory bodies. The category managers at pharma companies employ a combination of CROs and academia at different stages of drug development to optimise spend on DAL testing. Also, DAL data, both at preclinical and clinical stages, would immensely help regulatory bodies in product labelling and drug scheduling recommendation with the hope of reducing its misuse and dependence.

Prescription drugs hold the chance to be misused or used for nonmedical reasons and can lead to physical dependence and withdrawal symptoms. The symptoms thus results are generally noticed in the drugs that affect the central nervous system. Such drugs are found to have abuse potential or abuse liability.

Drug abuse liability study has surfaced on the safety pharmacology space in recent years as a result of numerous safety guidelines and discussion documents from regulatory bodies in the US and Europe. Increasing incidents about prescription drug abuse and the withdrawal prospective of many common drugs have necessitated development of evaluation procedures (both non -clinical & clinical) like abuse liability testing.

In the last decade, Asia, Europe, and Australia indicated major trouble with opiate dependence, South America primarily was affected by cocaine addiction , and Africans were treated most often for the addiction to cannabis. Only in North America was drug habit disseminated relatively uniformly between the use of opiates, cannabis, cocaine, amphetamines, and other narcotics.

What types of prescription drugs are abused?
Three types of drugs are most often abused:

Opioids: generally prescribed for pain relief
CNS depressants: barbiturates and benzodiazepines prescribed for anxiety or sleep problems (often referred to as sedatives or tranquilizers)
Stimulants: prescribed for attention-deficit hyperactivity disorder (ADHD), the sleep disorder narcolepsy, or obesity.

Market Overview
Drug abuse liability study has its significance across Pharma, bio-pharma, agrochemicals, medical devices and cosmetics industry. Recently, higher incidents of drug abuse have led regulatory body to solicit assessment of the safety profile of NCEs particularly for all new CNS-active medicinal products (parents + metabolites) that can cross the blood brain barrier (BBB ), interact with central targets and precipitate an abuse liability potential.

The estimated global market size for drug abuse liability study is around 1 .5bn USD growing steadily at ~3 percent. This market has a close impact with the CNS therapeutic area as all drug substance entering the CNS drug R & D space has to undergo abuse liability test.

There are three main types of studies that are typically employed to address abuse liability:
Drug discrimination -- This model is used to determine the properties of novel compounds with that of a known class of drugs or to determine if the novel compound can be distinguished. It is hence, used to identify the extent of similarity of the subjective effects of the new chemical entity to those of the known drugs of abuse, such as CNS stimulants or depressants.

Drug self-administration is a nonclinical model adopted to ascertain whether animals will work to get access to the direct injection of drugs. Administering the drug which induces the rewarding effect is the direct assessment of drug’s abuse liability. Amphetamine, morphine & cocaine are strongly positive in this test. Hence, it is used to directly measure the positive-reinforcing properties of the new chemical entity.

Drug dependence produces continued drug use in order to avoid negative feelings—physical or emotional—that occur when drug administration is stopped. Continued administration of a drug that produces dependence may be associated with the development of tolerance to the pharmacological effect of the drug. A positive signal in isolation doesn't necessarily indicate abuse potential. However, together with positive effects in the other assays , could contribute to the potential for abuse.

Exhibit:

Current service provision scenario in the market
Services in the drug abuse liability are provided by both academia and CROs. Service provision in the drug abuse liability testing could be 20-30% cheaper (could be even lesser depending on the particular area of interest) when done through academia but CROs are preferred due to two main reasons:

Speeds of completion- The work with the CROs are mainly business driven and customized as well. Hence, the focus is on the business outcome and timelines of client.
GLP Compliance- Most of the academia is non-GLP compliant and during the FDA reviews GLP compliance is mandatory. Hence, CROs are proactively chosen.

Though, academia and CROs are two separate entities but there can be subcontracting from CROs to academia due to
I. Greater scientific understanding on the subject by academia.
II. Better choice with protocol compliance & writing.
III. Interpretation of potential mechanisms of abuse.

However, CROs are mostly preferred for drug abuse liability studies due to the technology & expertise availability, regulatory compliance and capacity readiness. These CROs are also one stop shops for a battery of experiments required in abuse liability studies. As per pharma companies, it is more cost effective to rely on outside providers that can manage projects complexity and have an understanding of regulatory compliances.

Drug Abuse Liability Study: Compliance Scenario
The drug abuse liability testing is generally done as per GLP & non-GLP standard in the supply market greatly affecting the cost incurred & regulatory compliance requirement sought. However the quality of studies should be equivalent. Taking in to account a series of activities to evaluate the novel molecule with abuse potential, a two-tiered assessment is suggested by the regulatory body generally considered as Non-GLP (Tier1) or pharmacology & GLP (Tier2) or specific behavioral pharmacology studies.

Non-GLP Compliance:

Non-GLP studies are generally termed as tier1 study by regulatory body (EMA) and take in to account the testing of the novel molecule with abuse potential on account of chemical structure, PK/PD characteristics, pharmaceutical characteristics, etc.
Studies such as receptor-binding (in vitro), confirmation of binding & functional properties (in vivo) referred to under the first tier by European Medicines Agency as outlined under ICH S7A - largely need not meet the requirements of GLP.

GLP Compliance:

Studies for safety pharmacology are generally done with the GLP compliance which is largely considered as tier 2 studies as per regulatory body (EMA).
Specific behavioral pharmacology studies are done when the active substance has a novel mechanism of action & this is done on the basis of biochemical, pharmacological and clinical information already available through tier1 (non-GLP) test.

Market Practices:
Vendor Option: The service for drug abuse study is a very niche area and provided in the market by very few CROs and research oriented universities. Several independent consultants are also available in the market functioning in this space; however they again collaborate with same set of CROs for the service delivery.

CROs: These are the commercial services providers, having a greater understanding of the client’s requirement, regulatory practices & conformity (Good manufacturing practices (GMP) compliance) and proven expertise & experience.
Academia/University: These are the research centers with expertise of world leading disease scientists, technology experts, novel models etc. In abuse liability space, most of the academia is non-GMP compliant.
Consulting Firms: These are the group of Pharma consultants offering functional & regulatory affairs expertise and support services on the basis of their extensive experience & network of service providers.

Consulting firms are generally chosen for the abuse liability studies when a pharma company is planning to start these studies for very first time in order to understand the developing guidelines & standard operating procedure (SOP) and regulatory compliance. At the later stage they are not preferred because of their redundant use & added cost.

References

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM198650.pdf

http://www.fda.gov/downloads/AdvisoryCommittees /CommitteesMeetingMaterials/Drugs /DrugSafetyandRiskManagementAdvisoryCommittee/UCM337158.pdf

http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/abus /abuse_liability_abusif_usage_clin-eng.php

http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM180770.pdf

http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM180785.pdf

http://www.toxicology.org/isot/rc/nesot/docs/07Alper.pdf

http://www.ncbi.nlm.nih.gov/pubmed/10519736

http://www.ncbi.nlm.nih.gov/pubmed/

7 Reasons to switch to Vision Sensors
As the global manufacturing market continues to get more competitive, it is important to ensure that each factory is running at a peak level of efficiency. Any downtime due to process related malfunctions is considered non value-added downtime, which directly affects the company's profitability. Robust yet easy-to-use, self-contained vision sensors perform automated inspections that previously required costly and complex vision systems. The vision sensors solve simple inspection applications, are easy to use, fast and provide a simple pass/fail or go /no-go result.

Machine vision is an area that if setup correctly can reduce process inefficiencies. If your facility uses machine vision as robot guidance or inspection, there is always an area of improvement that can be investigated.

IDENTIFIES FEATURES PHOTOELECTRIC SENSORS CANNOT: Checker vision sensors can simplify inspections that would be troublesome for photoelectric sensors—such as the presence of tapped threads or weld nuts in an automotive assembly.
NO MECHANICAL FIXTURING: An object can be inspected in any position on the belt because the vision sensor is always looking for the part.
EXTERNAL TRIGGERS ARE NOT REQUIRED: Vision sensors overcome imprecise part positioning using patented multi-image analysis to determine if a part is present.
INSPECTS MULTIPLE PART FEATURES: There is no limit to the number of part features that a single Checker vision sensor can inspect. For example, a vision sensor can inspect for the presence of a straw and an insertion on a package of juice.
SET-UP, EDIT AND MONITOR INSPECTIONS on a smart display or a PC: Operators can set up new parameters or adjust existing inspections on a PC. Vision sensor activity can be displayed on a touch screen monitor making it easy for operator interaction on the factory floor.
ACCESSORIES OPTIMIZE IMAGE CONTRAST AND MINIMISE OBSCURING FEATURES: Vision sensors can be deployed with special lighting and filters to create better images and achieve more consistent and reliable results.
REQUIRES FEWER ADJUSTMENTS THAN PHOTOELECTRIC SENSORS : Unlike photoelectric sensors that require frequent adjustment , vision sensors can detect objects regardless of their speed and position on the line.