EURASIA RESEARCH PHARMA CORPORATION

Km 101 National Highway , San Leonardo. Nueva Ecija

(044) 604-30-0V0912..&38·!26! /09!7 892 3033 EfN'I·

SOP No. Page No.

Revision No. Sampling of Raw Materials Date Effective
Supersedes Review Date
Section. Quality Control

1. Purpose: To describe the procedure for sampling of raw materials

2. Copies to: Production, RM Warehouse, QC/QA

3. Abbreviations: QC/QA -Quality Control/Quality Assurance

RM -Raw Materials
SOP -Standard Operating Procedures

4 . Responsibility: QC Analyst, QC/QA Head

5. Materials/Facilities/Equipment to be used:
Raw materials
Sampling thief
Stainless scoop
polybag/bottles
pentel pen, black/blue
sample labels
Quarantine stickers
6. Reason/s for revision: Revision of process description to implement 100%
Sampling.
7. Process description:
7 .1 Prior to sampling.
7.1.1 Ensure RM sampling room is clean and free of extraneous
materials.
7.1.2 Ensure equipment used for sampling, such as, plastic
container and scoop are clean
7.1.3 QC Analyst wear complete uniform: lab gown,
mask, cap, gloves and working shoes following SOP # 2
7 .1.4 QC analyst washes hands following SOP # 1
7.1.5 Raw materials are transferred from quarantine area to RM
Sampling room.
7.2 Sampling Guidelines.
7.2.1. Implement 100% Sampling and inspection of material
deliveries-
APls and excipients.

7.2.1.1. Check the number of containers for each material

delivery.
7.2.1.2. Prepare pre-numbered sampling bags or sample
bottles [ Example for multiple container deliveries- pre
labels sample bags/ bottles as container No. 1 of 6,
2,6 ... 6 of 6)
7.2.1.3.Check the total quantity of sample required for the
material (Total sample taken should be sufficient for
chemical testing and retention; check requirement for
micro testing and ensure availability of tools and
materials for aseptic sampling.)
7.2.2.Guidelines for the number of samples to be taken from each
7.2.2.1. For raw materials ( powder) weighing 10kg or less, a
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 EURASIA RESEARCH PHARMA CORPORATION
Km 10 1 NahMAt Htgflway San Leonardo Nueva EoIa
(r)ouliQil l001.' 0'l:1 t.~ llt-1 1 091 7 891 JOH ,,.,..

single sample may be withdrawn from each container using

appropriate sample thief or spatula.
7.2.2.2 For APls (powder)weighing more than 10 kg but less than 50
kg , use a sample thief to withdraw sample from the middle
and
bottom of the container. Segregate and label samples as
(Example- Container. 1 of 2 - Middle)
7.2.2.3 For APls (powder) weighing 50 kg or more, use a sample thief
to withdraw sample from the top , middle and bottom of the
container. Segregate and label sample as directed.
7.3. Step by step sampling procedure
7.3.1. QC Analyst samples a total of 10 grams and pools sample
in a polybag/sample bottle.
7.3.2. Label sample with name of RM , Control NO., Sampled by
and date sampled.( see attached sampling form . )

7 .3.3. In cases of noxious materials for sampling, a safety

respirator instead of ordinary gauze mask is worn by QC Analyst.
7.3.4. In cases of materials irritating to the skin, long rubber gloves
instead of surgical gloves is worn by QC Analyst.
7.4 After sampling.
7.4.1 Properly close container to preserve integrity of contents,
label with"( sampled by QC, date sampled and sampled by )"
and return to quarantine area.
7.4.2 Samples are brought to QC Laboratory for testing and
evaluation.

8. End of document.

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 EURASIA RESEARCH PHARMA CORPORATION
Km 10 1 Nahooal Highway San Leonardo, Nueva Eo1a
Tt-"'4• {OUl(,04 ~l.'09~: ,ua 126 1 /0911891 lOll f ,nd ~ur~N>OOCCW,,

SOP No. Page No. -

-----
Rev1s10n No
Suoersedes
Requirements for Hiring Key
Personnel
Date Effective
Review Date
---

Section: Manufacturing Plant

1. Purpose: To describe the procedure for hiring key personnel.

2. Scope: This SOP is limited only to the requirements on how to hire key personnel for
plant
operations

3. Copies to: Production, Quality control, Quality Assurance and Engineering Departments

4. Abbreviations: SOP -Standard Operating Procedures

5. Responsibility: Human Resources Manager

6. Reason/s for revision: New

7. Process description:
7.1 QUALITY CONTROL MANAGER

Preferably a degree holder in pharmacy or chemistry, and at least 5 years

supervisory experience in the pharmaceutical or food industry. Should be
knowledgeable in chemical and microbiological analysis. Should be
knowledgeable in good laboratory practices (GLP) and GMP. Must have good
leadership and managerial skills.

Job Summary:

Oversees testing activities in the chemical and microbiological testing

laboratories. Assures that all products recommended for release to the market
meet pre-set and approved specifications. Responsible for approving raw
materials for production use, and testing of bulk, in process- and finished
products according to approved procedures.

7.2 QUALITY ASSURANCE MANAGER

Preferably a degree holder in pharmacy or chemistry, and at least 1O years

supervisory or managerial experience in production or quality control in a
pharmaceutical company. Should be knowledgeable in the regulatory
requirements for drug products (AO 43 and PIC/S Guidelines). Must be fluent in
English and have good leadership and managerial skills.

Job Summary:

Provides overall direction for compliance with Quality Systems and Good
Manufacturing Practices.

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 EURASIA RESEARCH PHARMA CORPORATION
Km 10 ? Nal,on;il Highway San Ll!On;m:!O Nueva Eqa
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t~ l M)I 'IO-Ot, c,q !.:'. ~'JS l .!t-1 / r:1917 -¥11 JO p . . ~ ¥ ' 0 0 lOM

7 3 PRODUCTION MANAGER

The produc tion manager should be a degree holder m pharmacy or chemistry

with at least 5 years of practical experience in the production of drug products.
have the experience and knowledge in pharmaceutical planning, pharmaceutical
equipment. GMP. leadership

Job Summary:

Production Manager is responsible for the production of Drug Products in

accordance with their quality specifications and strict adherence to GMP rules
within the required time and established product cost.

7 .4 ENGINEERING HEAD

Graduate of Engineering, preferably licensed. At least 5 years experience of

working in pharmaceutical manufacturing plant, preferably in production or
engineering. Knowledgeable in equipment use and maintenance.
Knowledgeable in GMP practices Physically fit and able to work with
minimal supervision

Job Summary:

Responsible for monitoring and supervision of engineering operations including

preventive maintenance programs, machine and building repairs. machine
trending, machine components inventory, and building assessment procedure
with proper documentation. Reviews internal or third party engineering reports
and takes the necessary decision and action to maintain continuous plant
operations.

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 EURASIA RESEARCH PHARMA CORPORATION
Km 101 Na11onal Highway San Leonardo. Nueva EciIa
1.,1,qs (uU)6041001/0921833- 1261 /09178'12lOH l~ -~~tO'T'

SOP No. Page No. 1 of 2

Revision No. Cleaning and Sanitation Date Effective
Supersedes Equipment Review Date

Section: Manufacturing Plant

1. Purpose: To provide guidelines for verifying the effectiveness of procedures

for cleaning and sanitization of equipment used in the
manufacturing.

2. Copies to: Production, Warehouse, Quality Control /Quality Aassurance

3. Abbreviations: QC/QA -Quality Control/Quality Assurance

4. Responsibility: QC Analyst, QC/QA Head

5. Materials/Facilities/Equipment to be used:

• De ionized Water
• 10% Liquid detergent solution
• Sponges, brushes, scrubbing materials
• Non-tinting, clean absorbent fabric
• Plastic wrap and tape
• Sanitizing agent: 70% Ethyl Alcohol Solution

6. Reason/s for revision: New

7. Process description:
7.1 ANALYTICAL METHODS

7.1.1. Appearance and Odor Test

Rinsing solutions will rinse out whatever residue is left
after
cleaning of any equipment. QC Analyst shall visually check
appearance and odor of last rinsing.
7.1.2. Microbial Test (To be done only on new equipment and during
equipment validation)
Microbial controls are carried out after the cleaning
procedure
for the determination of microbial population in sanitized
equipment. Samples after cleaning shall be taken only if
the complete cleaning procedure has been carried out.
Swab
samples should be taken upon drying of equipment.
Samples
are then microbiologically tested. Refer to specs for
microbial limit.
7.2. STANDARD CLEANING PROCEDURES
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 EURASIA RESEARCH PHARMA CORPORATION
Km 10 1 N1tional Highway, San Leonardo Nueva EoJa
1~• (044) ti(M ~ 1/ 0921 8:U- l lbl / r:91HJ92 10!1 (~ ~~ com

7.2.1. Cleaned and sanitized equipment not used within 24 hrs. shall
be
re-sanitized before using but ensure that all entry points of dirt

7. Process description: ( cont. )

7.2. must be securely wrapped/covered with plastic and undisturbed
for the duration of its storage. If this is not followed , or
equipment
gets dirty, cleaning and sanitization will be done again.
Equipment left empty of any product for three (3) days or more
shall be cleaned and sanitized prior to use.

7.3.Preparation of cleaning and sanitizing agents

7.3.1 70% Alcohol = 70ml Ethyl Alcohol in 30ml de ionized
Water.
7.3.2. 10% liquid Detergent Solution = 10ml Liquid Detergent in
90ml
deionized Water.
7.4.Cleaning Procedure
7.4.1. Dismantle or remove parts of equipment ,(ex. hoses. nozzle.
pipes, connector. fittings or valves) that come in contact with
the product to ensure thorough cleaning.
7.4.2. Remove dust, dirt or any possible source of contamination
coming from motor of _ _ _ _ _ _ _ _ _ _ _ __
7.4.3. Rinse component parts thoroughly with tap water to remove
product residues.
7.4.4. Scrub inner and outer parts of the equipment and its
components with 10% Liquid detergent solution.
7.4.5. Rinse thoroughly with de ionized water. Check for any
residue. If present, repeat scrubbing operation.
7.4.6. Flush with de ionized water three times.
7.4.7.Submit sample of last water rinse to QC for evaluation.
7.4.8. Assemble the parts of equipment and sanitized with 70%
ethyl alcohol
7.4.9 .. Notify QC for swab sampling.
7.4 .10. Ask the quality control Inspector to certify the cleanliness of
the equipment. He/ She issues a "certified clean • label
8. End of Document :

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 EURASIA RESEARCH PHARMA CORPORATION
Km 10 1 Nat,onal Highway San Leonardo N11e11a Eq;i
1()44) f>OA- 30-01 I Qq]2 US 116 l / 0017 -39 2 )0 D l ..,_

GUIDELINES FOR VALIDATION OF CLEANING PROCEDURE

1. Test for residues after cleaning

Cleaning procedures ~hould be adequately effective to remove re~idue~ of the ~anit1zing agent
and residues of materials used in the production. A surface swab is taken, and dispersed in water or
suitable solvent.

The extract is examined by TLC, colorimeter or microbiological assay. A blank test is also made.

2. Cleaning Validation

Cleaning procedures must adequately protect from cross-contamination the next product made
in common multi-use equipment.

Cleaning validation provides the assurance that equipment is clean and that product quality and
safety are maintained.

The program should set criteria for acceptance such as number of successful trials, appropriate
methods of sampling and maximum limit of allowable residues. In addition, there should be a
periodic review or audit of validated procedures and a comprehensive change control system.

The method of cleaning corresponds closely to the types of materials being removed from the
surface of the equipment; therefore, the residual limits used for cleaning validation are also related
to the toxicity/potency of the materials in question. Because potent drugs, drugs w ith high toxicity
or allergenic drugs can have adverse effects even at minute levels, cleaning, sampling and analysis
methods may need to be refined to a high degree of sensitivity to assure that such contaminants
have been completely removed. Consequently, more monitoring for validation and possibly more
frequent follow-up monitorings, may be necessary in those instances. In fact, it is operationally
easier to dedicate equipment and facility to the product rather than attempt to clean to extremely
low levels.

Certain classes of drugs such as beta-lactam antibiotics, already have regulatory requirements
for dedicated equipment and facilities. This class of products also should be manufactured in
isolated facilities.

Actual cleaning conditions and even worst-case conditions should be examined as part of the
validation protocol. For instance, if equipment sits for long periods of time before cleaning,
cleanability, and therefore the affect on validation is significant. Fluid product residues allowed to
dry on equipment surfaces can dramatically change the cleaning characteristics.

The validation protocol should set acceptance criteria for determining cleanliness. Analytical test
methods used to evaluate cleanliness should be documented or referenced in the protocol, including
information such as swabbing or rinse recovery, assay method detection level and normal linearity
and reproducibility information. Finally the protocol should specify the criteria by which the cleaning
procedure will be judge and indicate the manner in which the validation will be documented.

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 EURASIA RESEARCH PHARMA CORPORATION
Km 10 1 Na11ona1 Highway San Leonardo Nueva Eci1a
1044160l-l0-01.I 09l:: SJ.8 1261 / ,:,017 891 1033 £,...

3.0 Residue limits Determination

3.1 A rational method for determining cleaning vahdation acceptance hm1ts should be
established. Factors to consider are batch size, dosing, toxicology and equipment
size. There has been little or no guidance regarding ways to apply these factors to
cleaning valid ation work.

3.2 One method is to ensure that any carry-over of product residue meets the following
three criteria:
3.2.1 Dose Criterion (0.001)
No more than 0.001 dose of any product will appear in the maximum daily
dose of another product;

3.2.2 10 ppm Criterion

No more than 10 ppm of any product will appear in another product.

3.2.3 Visually Clean Criterion

No quantity of residue will be visible on the equipment after cleaning
procedures are performed.

Note:
A number of products meet the first two criteria at levels at which there still could
be visible residues left on the equipment after cleaning, e.g., sodium chloride USP
tablets. Yet it does not seem appropriate that residues could be visible on GMP
equipment even though it is labeled clean. Therefore, if the quantity of safe residue
is enough to be visible, the equipment mw,t be cleaned until no residues are seen.
Spiking studies have determined that the active ingredients in most drug products
are visible at approximately 100 mg per 5 x 5 cm swab area .

4.0 Sampling Method

4 .1 Swabbing, rinse sampling and placebo sampling constitute the three recognized
methods for cleaning validation sampling. Swabbing techniques include the use of a
swabbing material, often saturated with a solvent to physically sample the
equipment or facility surface. The use of solvent in conjunction with swabbing
provides both a chemical and physical removal of surface residues. Although water
is the most common agent, an organic solvent such as methanol or hexane may be
used instead. Having first determined the swabbing efficiency or recovery of the
drug of interest, a known area is sampled and the swab is analyzed through
appropriate analytical means.

4.2 Sites must be chosen carefully to be representative. This method also suffers from
being technique dependent and not applicable to inaccessible areas on the
equipment.

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 EURASIA RESEARCH PHARMA CORPORATION
Km 10 1 National Highway San Leonilfdo , Nue~a Eqa
l~ 10,U! 6CW 30-01..10':IU-8.33-l}f,J / 0017~2 lOH £,-1 ~ilho<-u,,,,

4.3 The rinse analysis method involves the use of a known volume of solvent to rinse the
equipment surface area.

4.4 The solvent may be an organic such as methanol or it might be the final water rinse
that commonly marks the last step of the cleaning process. The solvent is then
collected and analyzed. The advantage of this rinse method 1s that, 1f performed
correctly, it yields a measurement for the entire equipment surface area. However,
the solvent chosen must be one that ensures a high recovery of the contaminate of
interest. In fact, one recognized weakness of the rinse analysis method is that the
contaminate may not dissolve or may suffer dilution problems and thus not yield a
true measurement. Although rinsing is not as rugged (physical) as swabbing. it
nevertheless has the advantage of being able to cover large surface areas and reach
less-accessible regions. For precisely those reasons, it is commonly used in bulk
processing facilities.

4.5 The placebo sampling method involves determining residues on equipment by

processing a placebo batch through the equipment after cleaning and then testing
the placebo for the contaminant. This method may not generally be accepted by
regulatory reviewers.
5.0 Assay Method
5.1 A close relationship must exist between the residue limit that has been set and the
assay method used to verify the cleanliness of equipment. Assuming limit is
analytically feasible, a variety of methods are available.
5.2 High-Performance Liquid Chromatography (HPLC) has the capability for the lowest
level of detection, but it is also the most costly. Spectrophotometric methods (UV)
and Thin-Layer Chromatography (TLC) generate lower costs, but at the expense of
detection capability. The importance of determining the detection capability of the
specific selected method should not be overlooked. The detection level is
considered part of the information one would be expected to have as part of the
cleaning validation assay documentation.

5.3 Methods such as HPLC, nc and UV have long-established acceptance. Although

generally used for swabbing analysis of drug substance or product excipient
residuals, these methods can be applied equally well to solvent-rinse or water-rrnse
analyses.

5.4 Total Organic Carbon (TOC) analysis is a relatively new method generating a great
deal of interest because of its potential application for biopharmaceuticals and
residuals cleaning agents, in addition to active drug contaminate~.

5.5 Enzyme-Linked lmmunosorbent Assay {ELISA), on the other hand, is a high-cost, time
consuming method that has only been applied to biopharmaceuticals. Although it is
a highly specific method, it is nevertheless unable to detect denatured protein.

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 5.6 A number of the remaining methods such as conductivity, pH, gravimetric and
ti1ration - used mainly for residual cleaning agent measurement, an area of
111creasrng concern for sterile and b,opharmaceutical products. Conductivity and pH
analysis can be used online for confirmation of cleaning agent residuals. The last
two methods such as light microscopic examination and visual detection are used
marnly for detecting cross contammation.
6.0 Change Control

All aspects of cleaning are subject to change control. Cleaning procedures, assay methods,
equipment, detergents, product formulations and processing should be documented at the
time of validation. Subsequent changes to these items, then, require review, approval and
possibly revalidation.

7.0 Re-evaluation and Audrting

Even after a satisfactory cleaning process has been put in place, it is important to perform
regular checks to verify that the process is performing in the same manner as when it was
validated. To reconfirm validated status, some subset of validation must be repeated at
specified intervals, either in the form of an audit or other periodic monitoring. It may be
necessary to reviews the entire cleaning procedure, including the operators. The original
validation work, toxicity of the drug and type of cleaning process should be taken into
account when deciding how frequently to audit. In addition, it may be useful to track the
cleaning agents themselves and assure that no changes have been made to their
formulations.

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